rs779985493

Positions:

• chr1-241500598-T-TGAGTGA

Variant summary

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

The NM_000143.4(FH):​c.1237-9_1237-8insTCACTC 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 0.000114 in 1,411,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: FH NM_000143.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0410

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 1-241500598-T-TGAGTGA is Benign according to our data. Variant chr1-241500598-T-TGAGTGA is described in ClinVar as [Likely_benign]. Clinvar id is 237109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000671 (39/58154) while in subpopulation EAS AF= 0.0135 (36/2674). AF 95% confidence interval is 0.01. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4	c.1237-9_1237-8insTCACTC		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.1237-9_1237-8insTCACTC		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000143.4	ENSP00000355518	P1

Frequencies

GnomAD3 genomes AF: 0.000671 AC: 39 AN: 58090 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0134

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00236

GnomAD4 exome AF: 0.0000901 AC: 122 AN: 1353472 Hom.: 0 Cov.: 33 AF XY: 0.0000755 AC XY: 51 AN XY: 675532

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00227

Gnomad4 SAS exome AF: 0.000108

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000292

Gnomad4 OTH exome AF: 0.000429

GnomAD4 genome AF: 0.000671 AC: 39 AN: 58154 Hom.: 0 Cov.: 30 AF XY: 0.000639 AC XY: 18 AN XY: 28174

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000158

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00232

Alfa AF: 0.0000843 Hom.: 0

Asia WGS AF: 0.00463 AC: 16 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary leiomyomatosis and renal cell cancer Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Fumarase deficiency Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 26, 2019	- -
Likely benign, 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

Genetic Services Laboratory, University of Chicago

Feb 03, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

FH-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 13, 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: rs779985493; hg19: chr1-241663898;