1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGA

Position:

• chr1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The ENST00000366560.4(FH):​c.1237-14_1237-13del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,479,644 control chromosomes in the GnomAD database, including 99 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.022 (96 hom., cov: 0)
  • Exomes 𝑓: 0.041 (3 hom.)
• Consequence: FH ENST00000366560.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 2.18

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 1-241500602-TGA-T is Benign according to our data. Variant chr1-241500602-TGA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296871.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}. Variant chr1-241500602-TGA-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4	c.1237-14_1237-13del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.1237-14_1237-13del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000143.4	ENSP00000355518	P1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 2928 AN: 133722 Hom.: 96 Cov.: 0

Gnomad AFR AF: 0.0719

Gnomad AMI AF: 0.00115

Gnomad AMR AF: 0.00935

Gnomad ASJ AF: 0.00244

Gnomad EAS AF: 0.00629

Gnomad SAS AF: 0.00590

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00694

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.0408 AC: 54855 AN: 1345834 Hom.: 3 AF XY: 0.0412 AC XY: 27588 AN XY: 669888

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.0807

Gnomad4 ASJ exome AF: 0.0668

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.0425

Gnomad4 FIN exome AF: 0.0526

Gnomad4 NFE exome AF: 0.0329

Gnomad4 OTH exome AF: 0.0476

GnomAD4 genome AF: 0.0220 AC: 2939 AN: 133810 Hom.: 96 Cov.: 0 AF XY: 0.0219 AC XY: 1396 AN XY: 63822

Gnomad4 AFR AF: 0.0720

Gnomad4 AMR AF: 0.00942

Gnomad4 ASJ AF: 0.00244

Gnomad4 EAS AF: 0.00652

Gnomad4 SAS AF: 0.00543

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.00303

Gnomad4 OTH AF: 0.0122

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary leiomyomatosis and renal cell cancer Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 13, 2014	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 16, 2021	- -

Fumarase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

FH-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2021

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

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: rs144131869; hg19: chr1-241663902;