1-241504223-C-T

Position:

• chr1-241504223-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000143.4(FH):​c.927G>A​(p.Pro309Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,613,886 control chromosomes in the GnomAD database, including 1,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P309P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.027 (78 hom., cov: 32)
  • Exomes 𝑓: 0.029 (954 hom.)
• Consequence: FH NM_000143.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 0.464

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 1-241504223-C-T is Benign according to our data. Variant chr1-241504223-C-T is described in ClinVar as [Benign]. Clinvar id is 137370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241504223-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.464 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4	c.927G>A	p.Pro309Pro	synonymous_variant	7/10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.927G>A	p.Pro309Pro	synonymous_variant	7/10	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes AF: 0.0268 AC: 4073 AN: 152074 Hom.: 79 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.0481

Gnomad SAS AF: 0.0855

Gnomad FIN AF: 0.0260

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0346 AC: 8674 AN: 251020 Hom.: 232 AF XY: 0.0368 AC XY: 4996 AN XY: 135650

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0536

Gnomad EAS exome AF: 0.0450

Gnomad SAS exome AF: 0.0864

Gnomad FIN exome AF: 0.0229

Gnomad NFE exome AF: 0.0235

Gnomad OTH exome AF: 0.0351

GnomAD4 exome AF: 0.0290 AC: 42386 AN: 1461692 Hom.: 954 Cov.: 33 AF XY: 0.0308 AC XY: 22372 AN XY: 727144

Gnomad4 AFR exome AF: 0.0188

Gnomad4 AMR exome AF: 0.0270

Gnomad4 ASJ exome AF: 0.0539

Gnomad4 EAS exome AF: 0.0590

Gnomad4 SAS exome AF: 0.0838

Gnomad4 FIN exome AF: 0.0247

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0350

GnomAD4 genome AF: 0.0267 AC: 4066 AN: 152194 Hom.: 78 Cov.: 32 AF XY: 0.0273 AC XY: 2030 AN XY: 74408

Gnomad4 AFR AF: 0.0187

Gnomad4 AMR AF: 0.0228

Gnomad4 ASJ AF: 0.0565

Gnomad4 EAS AF: 0.0480

Gnomad4 SAS AF: 0.0844

Gnomad4 FIN AF: 0.0260

Gnomad4 NFE AF: 0.0246

Gnomad4 OTH AF: 0.0406

Alfa AF: 0.0268 Hom.: 33

Bravo AF: 0.0244

Asia WGS AF: 0.0830 AC: 290 AN: 3478

EpiCase AF: 0.0232

EpiControl AF: 0.0251

ClinVar

Significance: Benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2012	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 02, 2014	- -

not provided Benign:5

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2016	Variant summary: The FH variant, c.927G>A (p.Pro309Pro) causes a synonymous change involving a non-conserved nucleotide with 5/5 in silico tools via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4203/120454 (1/28, 104 homozygotes), which exceeds the estimated maximum expected allele frequency for a pathogenic FH variant of 1/400000. In addition, multiple reputable clinical laboratories cite the variant as "benign." Therefore, the variant of interest is classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary leiomyomatosis and renal cell cancer Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Fumarase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2014

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
BayesDel_noAF	Benign	-0.27
CADD	Benign	11
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs61737760; hg19: chr1-241667523; COSMIC: COSV63817570;