1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_000143.4(FH):c.1237-14_1237-13dupTC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.10 ( 702 hom., cov: 0)

Exomes 𝑓: 0.16 ( 62 hom. )

Failed GnomAD Quality Control

Consequence

FH
NM_000143.4 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:8

Conservation

PhyloP100: -0.993

Publications

5 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 -9 ACMG points.

BP6

Variant 1-241500602-T-TGA is Benign according to our data. Variant chr1-241500602-T-TGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296865.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000143.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	NM_000143.4	MANE Select	c.1237-14_1237-13dupTC		intron	N/A	NP_000134.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FH	ENST00000366560.4	TSL:1 MANE Select	c.1237-14_1237-13dupTC	intron	N/A	ENSP00000355518.4
FH	ENST00000682567.1		n.4623_4624dupTC	non_coding_transcript_exon	Exon 7 of 8
FH	ENST00000683521.1		c.1237-14_1237-13dupTC	intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

13380

AN:

133644

Hom.:

702

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0600

Gnomad AMI

AF:

0.154

Gnomad AMR

AF:

0.0775

Gnomad ASJ

AF:

0.0991

Gnomad EAS

AF:

0.106

Gnomad SAS

AF:

0.0591

Gnomad FIN

AF:

0.161

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.0840

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.157

AC:

209116

AN:

1328574

Hom.:

Cov.:

AF XY:

0.158

AC XY:

104355

AN XY:

661282

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0739

AC:

2274

AN:

30792

American (AMR)

AF:

0.134

AC:

5429

AN:

40622

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

3465

AN:

23990

East Asian (EAS)

AF:

0.112

AC:

4159

AN:

37028

South Asian (SAS)

AF:

0.155

AC:

12189

AN:

78750

European-Finnish (FIN)

AF:

0.172

AC:

6716

AN:

38974

Middle Eastern (MID)

AF:

0.130

AC:

538

AN:

4140

European-Non Finnish (NFE)

AF:

0.163

AC:

166177

AN:

1019168

Other (OTH)

AF:

0.148

AC:

8169

AN:

55110

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.359

Heterozygous variant carriers

10262

20525

30787

41050

51312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6192

12384

18576

24768

30960

<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:

0.100

AC:

13381

AN:

133730

Hom.:

702

Cov.:

AF XY:

0.101

AC XY:

6462

AN XY:

63792

show subpopulations

African (AFR)

AF:

0.0599

AC:

2093

AN:

34948

American (AMR)

AF:

0.0773

AC:

1017

AN:

13156

Ashkenazi Jewish (ASJ)

AF:

0.0991

AC:

324

AN:

3270

East Asian (EAS)

AF:

0.106

AC:

487

AN:

4594

South Asian (SAS)

AF:

0.0593

AC:

240

AN:

4046

European-Finnish (FIN)

AF:

0.161

AC:

1136

AN:

7060

Middle Eastern (MID)

AF:

0.111

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.122

AC:

7769

AN:

63730

Other (OTH)

AF:

0.0848

AC:

152

AN:

1792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

529

1058

1588

2117

2646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<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:

0.177

Hom.:

226

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: See variant below

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Hereditary leiomyomatosis and renal cell cancer

Uncertain:2Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 03, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Fumarase deficiency

Uncertain:1Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:2

Dec 18, 2014

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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.

Jun 07, 2021

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

not provided

Benign:1

Aug 09, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.99

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over