chr1-241500602-T-TGAGAGAGAGAGAGA

Position:

• chr1-241500602-T-TGAGAGAGAGAGAGA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000143.4(FH):​c.1237-13_1237-12insTCTCTCTCTCTCTC 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 0.043 (158 hom., cov: 0)
  • Exomes 𝑓: 0.023 (154 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts 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 -8 ACMG points.

• BP6: Variant 1-241500602-T-TGAGAGAGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGAGAGAGA is described in ClinVar as [Likely_benign]. Clinvar id is 1237054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 5796 AN: 133480 Hom.: 158 Cov.: 0

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.00672

Gnomad EAS AF: 0.00608

Gnomad SAS AF: 0.0121

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.0174

Gnomad NFE AF: 0.0596

Gnomad OTH AF: 0.0388

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0230 AC: 30872 AN: 1341288 Hom.: 154 Cov.: 48 AF XY: 0.0223 AC XY: 14863 AN XY: 667814

Gnomad4 AFR exome AF: 0.0157

Gnomad4 AMR exome AF: 0.00732

Gnomad4 ASJ exome AF: 0.00578

Gnomad4 EAS exome AF: 0.00218

Gnomad4 SAS exome AF: 0.00545

Gnomad4 FIN exome AF: 0.0245

Gnomad4 NFE exome AF: 0.0265

Gnomad4 OTH exome AF: 0.0206

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0434 AC: 5796 AN: 133570 Hom.: 158 Cov.: 0 AF XY: 0.0408 AC XY: 2600 AN XY: 63702

Gnomad4 AFR AF: 0.0285

Gnomad4 AMR AF: 0.0270

Gnomad4 ASJ AF: 0.00672

Gnomad4 EAS AF: 0.00609

Gnomad4 SAS AF: 0.0123

Gnomad4 FIN AF: 0.0475

Gnomad4 NFE AF: 0.0596

Gnomad4 OTH AF: 0.0384

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 08, 2018	- -

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;