1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGA

Position:

• chr1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000143.4(FH):​c.1237-22_1237-13del 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 0.0000912 in 1,490,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000075 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: FH NM_000143.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.18

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 1-241500602-TGAGAGAGAGA-T is Benign according to our data. Variant chr1-241500602-TGAGAGAGAGA-T is described in ClinVar as [Likely_benign]. Clinvar id is 2575507.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4	c.1237-22_1237-13del		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.1237-22_1237-13del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000143.4	ENSP00000355518	P1

Frequencies

GnomAD3 genomes AF: 0.0000747 AC: 10 AN: 133802 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000760

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000217

Gnomad SAS AF: 0.000246

Gnomad FIN AF: 0.000141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000784

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000929 AC: 126 AN: 1356806 Hom.: 0 AF XY: 0.0000755 AC XY: 51 AN XY: 675462

Gnomad4 AFR exome AF: 0.000767

Gnomad4 AMR exome AF: 0.000265

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000530

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000682

Gnomad4 OTH exome AF: 0.000142

GnomAD4 genome AF: 0.0000747 AC: 10 AN: 133892 Hom.: 0 Cov.: 0 AF XY: 0.000125 AC XY: 8 AN XY: 63870

Gnomad4 AFR AF: 0.0000286

Gnomad4 AMR AF: 0.0000759

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000217

Gnomad4 SAS AF: 0.000247

Gnomad4 FIN AF: 0.000141

Gnomad4 NFE AF: 0.0000784

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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

- -

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;