chr1-241500602-T-TGAGAGAGAGAGA

Position:

• chr1-241500602-T-TGAGAGAGAGAGA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000143.4(FH):​c.1237-13_1237-12insTCTCTCTCTCTC 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 0.020 (36 hom., cov: 0)
  • Exomes 𝑓: 0.023 (155 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:3 B:5
• 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-TGAGAGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGAGAGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296870.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0201 (2695/133752) while in subpopulation EAS AF= 0.0309 (142/4596). AF 95% confidence interval is 0.0268. There are 36 homozygotes in gnomad4. There are 1234 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2695 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4	c.1237-13_1237-12insTCTCTCTCTCTC		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.1237-13_1237-12insTCTCTCTCTCTC		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000143.4	ENSP00000355518	P1

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 2691 AN: 133662 Hom.: 36 Cov.: 0

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.00346

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.0308

Gnomad SAS AF: 0.0167

Gnomad FIN AF: 0.00592

Gnomad MID AF: 0.0105

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0186

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0232 AC: 31148 AN: 1340688 Hom.: 155 Cov.: 48 AF XY: 0.0228 AC XY: 15225 AN XY: 667398

Gnomad4 AFR exome AF: 0.0213

Gnomad4 AMR exome AF: 0.00976

Gnomad4 ASJ exome AF: 0.00871

Gnomad4 EAS exome AF: 0.0105

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.0193

Gnomad4 NFE exome AF: 0.0258

Gnomad4 OTH exome AF: 0.0219

GnomAD4 genome AF: 0.0201 AC: 2695 AN: 133752 Hom.: 36 Cov.: 0 AF XY: 0.0193 AC XY: 1234 AN XY: 63774

Gnomad4 AFR AF: 0.0264

Gnomad4 AMR AF: 0.0161

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.0309

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.00592

Gnomad4 NFE AF: 0.0192

Gnomad4 OTH AF: 0.0184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

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

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 05, 2021

- -

FH-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2023

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

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;