chr1-241500602-T-TGAGAGAGAGAGAGAGA

Position:

• chr1-241500602-T-TGAGAGAGAGAGAGAGA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000366560.4(FH):​c.1237-13_1237-12insTCTCTCTCTCTCTCTC variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (12 hom., cov: 0)
  • Exomes 𝑓: 0.0033 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH ENST00000366560.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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 -16 ACMG points.

• BP6: Variant 1-241500602-T-TGAGAGAGAGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGAGAGAGAGA is described in ClinVar as [Likely_benign]. Clinvar id is 1692238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00884 (1183/133790) while in subpopulation AFR AF= 0.0175 (610/34908). AF 95% confidence interval is 0.0163. There are 12 homozygotes in gnomad4. There are 535 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1183 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00886 AC: 1184 AN: 133700 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00441

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00130

Gnomad SAS AF: 0.000984

Gnomad FIN AF: 0.00183

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00507

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00329 AC: 4449 AN: 1353852 Hom.: 11 Cov.: 48 AF XY: 0.00327 AC XY: 2207 AN XY: 673992

Gnomad4 AFR exome AF: 0.00796

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00620

Gnomad4 EAS exome AF: 0.000345

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.00368

Gnomad4 NFE exome AF: 0.00340

Gnomad4 OTH exome AF: 0.00367

GnomAD4 genome AF: 0.00884 AC: 1183 AN: 133790 Hom.: 12 Cov.: 0 AF XY: 0.00838 AC XY: 535 AN XY: 63812

Gnomad4 AFR AF: 0.0175

Gnomad4 AMR AF: 0.00433

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00130

Gnomad4 SAS AF: 0.000987

Gnomad4 FIN AF: 0.00183

Gnomad4 NFE AF: 0.00707

Gnomad4 OTH AF: 0.00502

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 19, 2021

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 01, 2021

- -

FH-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 04, 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

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;