NM_000143.4:c.1237-7C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000143.4(FH):c.1237-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000321 in 1,586,462 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000018 ( 1 hom. )

Consequence

FH
NM_000143.4 splice_region, intron

Scores

Splicing: ADA: 0.00003106

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.345

Publications

0 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.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 1-241500597-G-A is Benign according to our data. Variant chr1-241500597-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 418591.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000197 (25/126810) while in subpopulation AFR AF = 0.000708 (24/33890). AF 95% confidence interval is 0.000488. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4 link	c.1237-7C>T		splice_region_variant, intron_variant	Intron 8 of 9	ENST00000366560.4	NP_000134.2	P07954-1A0A0S2Z4C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4 link	c.1237-7C>T		splice_region_variant, intron_variant	Intron 8 of 9	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

126678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000711

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000324

AC:

AN:

247132

AF XY:

0.0000299

show subpopulations

Gnomad AFR exome

AF:

0.000501

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1459652

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726212

show subpopulations

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

African (AFR)

AF:

0.000568

AC:

AN:

33436

American (AMR)

AF:

0.0000447

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51848

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111770

Other (OTH)

AF:

0.0000829

AC:

AN:

60340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000325627), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.367

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000197

AC:

AN:

126810

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

AN XY:

61400

show subpopulations

African (AFR)

AF:

0.000708

AC:

AN:

33890

American (AMR)

AF:

0.0000848

AC:

AN:

11786

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3120

East Asian (EAS)

AF:

0.00

AC:

AN:

4420

South Asian (SAS)

AF:

0.00

AC:

AN:

3426

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

59052

Other (OTH)

AF:

0.00

AC:

AN:

1662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.000337

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jun 22, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted FH c.1237-7C>T or IVS8-7C>T and consists of a C>T nucleotide substitution at the -7 position of intron 8 of the FH gene. Multiple splice prediction models are uninformative for this variant. In the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FH c.1237-7C>T was observed with an allele frequency of 0.2% (7/4406) in African Americans in the NHLBI Exome Sequencing Project. The cytosine (C) nucleotide that is altered is not conserved across species. Based on currently available information, it is unclear whether FH c.1237-7C>T is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2022

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:1

Sep 11, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary cancer-predisposing syndrome

Benign:1

Mar 15, 2022

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

FH-related disorder

Benign:1

Jan 23, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.92

(source)

DANN

Benign

0.64

PhyloP100

-0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000031

dbscSNV1_RF

Benign

0.0040

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