rs187226800

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000143.4(FH):c.77C>T(p.Pro26Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000782 in 1,548,066 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P26P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00082 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 21 hom. )

Consequence

FH
NM_000143.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 3.19

Publications

6 publications found

Variant links:

Genes affected

FH (HGNC:3700): (fumarate hydratase) The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy. [provided by RefSeq, Jul 2008]

FH Gene-Disease associations (from GenCC):

hereditary leiomyomatosis and renal cell cancer
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
fumaric aciduria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
pheochromocytoma-paraganglioma
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
leiomyosarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 132 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.2708 (below the threshold of 3.09). Trascript score misZ: 2.0634 (below the threshold of 3.09). GenCC associations: The gene is linked to fumaric aciduria, hereditary leiomyomatosis and renal cell cancer, hereditary pheochromocytoma-paraganglioma, leiomyosarcoma, pheochromocytoma-paraganglioma.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060353875).

BP6

Variant 1-241519646-G-A is Benign according to our data. Variant chr1-241519646-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00082 (125/152368) while in subpopulation EAS AF = 0.023 (119/5184). AF 95% confidence interval is 0.0196. There are 1 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 21 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4 link	c.77C>T	p.Pro26Leu	missense_variant	Exon 1 of 10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4 link	c.77C>T	p.Pro26Leu	missense_variant	Exon 1 of 10	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes

AF:

0.000834

AC:

127

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0233

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00215

AC:

313

AN:

145660

AF XY:

0.00210

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0282

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000755

Gnomad OTH exome

AF:

0.000960

GnomAD4 exome

AF:

0.000777

AC:

1085

AN:

1395698

Hom.:

Cov.:

AF XY:

0.000769

AC XY:

529

AN XY:

688330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31468

American (AMR)

AF:

0.0000280

AC:

AN:

35662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25148

East Asian (EAS)

AF:

0.0276

AC:

984

AN:

35708

South Asian (SAS)

AF:

0.000405

AC:

AN:

79068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48322

Middle Eastern (MID)

AF:

0.000246

AC:

AN:

4064

European-Non Finnish (NFE)

AF:

0.0000185

AC:

AN:

1078488

Other (OTH)

AF:

0.000814

AC:

AN:

57770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

120

181

241

301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000820

AC:

125

AN:

152368

Hom.:

Cov.:

AF XY:

0.000926

AC XY:

AN XY:

74524

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41592

American (AMR)

AF:

0.0000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0230

AC:

119

AN:

5184

South Asian (SAS)

AF:

0.000621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000299

Hom.:

Bravo

AF:

0.000960

ExAC

AF:

0.000623

AC:

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Jul 10, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 16, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FH c.77C>T (p.Pro26Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 145660 control chromosomes, predominantly at a frequency of 0.028 within the East Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11200 fold of the estimated maximal expected allele frequency for a pathogenic variant in FH causing Hereditary Leiomyomatosis and Renal Cell Cancer phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.77C>T has been reported in the literature (e.g. Pan_2019). Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary leiomyomatosis and renal cell cancer

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 17, 2024

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer

Benign:2

May 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 25, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fumarase deficiency

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:1

Sep 30, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.27

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0060

MetaSVM

Pathogenic

0.81

MutationAssessor

Benign

0.0

PhyloP100

3.2

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.62

REVEL

Uncertain

0.39

Sift

Benign

0.34

Sift4G

Benign

0.42

Polyphen

0.0

Vest4

0.35

MVP

0.82

MPC

0.29

ClinPred

0.028

GERP RS

0.90

PromoterAI

0.042

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.034

gMVP

0.40

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over