1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGAGAGA

Position:

• chr1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGAGAGA

Variant summary

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

The NM_000143.4(FH):​c.1237-13_1237-12insTCTCTCTC 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 0.077 (490 hom., cov: 0)
  • Exomes 𝑓: 0.047 (196 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: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 -9 ACMG points.

• BP6: Variant 1-241500602-T-TGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296868.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0772 AC: 10305 AN: 133414 Hom.: 491 Cov.: 0

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0719

Gnomad AMR AF: 0.0702

Gnomad ASJ AF: 0.0939

Gnomad EAS AF: 0.0866

Gnomad SAS AF: 0.0570

Gnomad FIN AF: 0.0590

Gnomad MID AF: 0.0347

Gnomad NFE AF: 0.0532

Gnomad OTH AF: 0.0626

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0473 AC: 63344 AN: 1338926 Hom.: 196 Cov.: 48 AF XY: 0.0469 AC XY: 31276 AN XY: 666266

Gnomad4 AFR exome AF: 0.0945

Gnomad4 AMR exome AF: 0.0380

Gnomad4 ASJ exome AF: 0.0556

Gnomad4 EAS exome AF: 0.0627

Gnomad4 SAS exome AF: 0.0514

Gnomad4 FIN exome AF: 0.0399

Gnomad4 NFE exome AF: 0.0453

Gnomad4 OTH exome AF: 0.0514

GnomAD4 genome AF: 0.0772 AC: 10309 AN: 133506 Hom.: 490 Cov.: 0 AF XY: 0.0777 AC XY: 4947 AN XY: 63682

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.0701

Gnomad4 ASJ AF: 0.0939

Gnomad4 EAS AF: 0.0863

Gnomad4 SAS AF: 0.0564

Gnomad4 FIN AF: 0.0590

Gnomad4 NFE AF: 0.0532

Gnomad4 OTH AF: 0.0619

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

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 Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2019	- -
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

- -

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;