rs1553340717

Variant names:

• chr1-241500598-T-TGA
• rs1553340717
• NM_000143.4:c.1237-10_1237-9dupTC

Your query was ambiguous. Multiple possible variants found:

• chr1-241500598-T-TGA
• chr1-241500598-T-TGAGA
• chr1-241500598-T-TGAGAGA
• chr1-241500598-T-TGAGAGAGA
• chr1-241500598-T-TGAGAGAGAGAGAGA
• chr1-241500598-T-TGAGAGAGAGAGAGAGA
• chr1-241500598-T-TGAGAGAGAGAGAGAGAGA
• chr1-241500598-T-TGAGCGA
• chr1-241500598-T-TGAGCGAGAGAGAGA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000143.4(FH):​c.1237-10_1237-9dupTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000591 in 1,353,658 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0410
• Publications: 0 publications found

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]

FH Gene-Disease associations (from GenCC):

• hereditary leiomyomatosis and renal cell cancer

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• fumaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pheochromocytoma-paraganglioma

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• leiomyosarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-241500598-T-TGA is Benign according to our data. Variant chr1-241500598-T-TGA is described in ClinVar as Likely_benign. ClinVar VariationId is 413616.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4	c.1237-10_1237-9dupTC		intron_variant	Intron 8 of 9	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.1237-10_1237-9dupTC		intron_variant	Intron 8 of 9	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000910 AC: 2 AN: 219664 AF XY: 0.00000838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000311

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000591 AC: 8 AN: 1353658 Hom.: 0 Cov.: 33 AF XY: 0.00000740 AC XY: 5 AN XY: 675604

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31384

American (AMR) AF: 0.0000230 AC: 1 AN: 43518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24826

East Asian (EAS) AF: 0.00 AC: 0 AN: 38100

South Asian (SAS) AF: 0.0000602 AC: 5 AN: 83092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4862

European-Non Finnish (NFE) AF: 0.00000195 AC: 2 AN: 1025880

Other (OTH) AF: 0.00 AC: 0 AN: 56016

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000545418), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.041
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553340717; hg19: chr1-241663898;