1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGAGA

Position:

• chr1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGAGA

Variant summary

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

The ENST00000366560.4(FH):​c.1237-13_1237-12insTCTCTC 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 0.20 (2680 hom., cov: 0)
  • Exomes 𝑓: 0.15 (564 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH ENST00000366560.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• 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-TGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296867.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=4}.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.202 AC: 26994 AN: 133502 Hom.: 2678 Cov.: 0

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.199

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.152 AC: 202299 AN: 1326574 Hom.: 564 Cov.: 48 AF XY: 0.151 AC XY: 99564 AN XY: 659940

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.202 AC: 27016 AN: 133592 Hom.: 2680 Cov.: 0 AF XY: 0.201 AC XY: 12811 AN XY: 63710

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.174

Gnomad4 NFE AF: 0.226

Gnomad4 OTH AF: 0.200

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

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 specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2019	- -

Fumarase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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;