1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGA

Position:

• chr1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGA

Variant summary

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

The NM_000143.4(FH):​c.1237-13_1237-12insTC variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7
• Conservation: PhyloP100: -0.993

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-T-TGA is Benign according to our data. Variant chr1-241500602-T-TGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296865.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=4, Likely_benign=1}.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FH	NM_000143.4	c.1237-13_1237-12insTC		splice_polypyrimidine_tract_variant, intron_variant		ENST00000366560.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FH	ENST00000366560.4	c.1237-13_1237-12insTC		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000143.4	P1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 13380 AN: 133644 Hom.: 702 Cov.: 0

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.: 62 Cov.: 48 AF XY: 0.158 AC XY: 104355 AN XY: 661282

Gnomad4 AFR exome AF: 0.0739

Gnomad4 AMR exome AF: 0.134

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.100 AC: 13381 AN: 133730 Hom.: 702 Cov.: 0 AF XY: 0.101 AC XY: 6462 AN XY: 63792

Gnomad4 AFR AF: 0.0599

Gnomad4 AMR AF: 0.0773

Gnomad4 ASJ AF: 0.0991

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.0593

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.0848

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

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	- -

Fumarase deficiency Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 18, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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;