1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

Position:

• chr1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

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.1237-32_1237-13dupTCTCTCTCTCTCTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 0)
  • Exomes 𝑓: 0.00040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -16 ACMG points.

• BP6: Variant 1-241500602-T-TGAGAGAGAGAGAGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGAGAGAGAGAGAGA is described in ClinVar as [Likely_benign]. Clinvar id is 1692240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00177 (237/133868) while in subpopulation AFR AF= 0.00383 (134/34954). AF 95% confidence interval is 0.00331. There are 3 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 237 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4	c.1237-32_1237-13dupTCTCTCTCTCTCTCTCTCTC		intron_variant		ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.1237-32_1237-13dupTCTCTCTCTCTCTCTCTCTC		intron_variant		1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 237 AN: 133778 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000228

Gnomad ASJ AF: 0.00153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000246

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00694

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000398 AC: 540 AN: 1356380 Hom.: 0 Cov.: 48 AF XY: 0.000379 AC XY: 256 AN XY: 675240

Gnomad4 AFR exome AF: 0.00112

Gnomad4 AMR exome AF: 0.000193

Gnomad4 ASJ exome AF: 0.000982

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000161

Gnomad4 FIN exome AF: 0.000226

Gnomad4 NFE exome AF: 0.000405

Gnomad4 OTH exome AF: 0.000515

GnomAD4 genome AF: 0.00177 AC: 237 AN: 133868 Hom.: 3 Cov.: 0 AF XY: 0.00169 AC XY: 108 AN XY: 63858

Gnomad4 AFR AF: 0.00383

Gnomad4 AMR AF: 0.000228

Gnomad4 ASJ AF: 0.00153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000247

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 14, 2021

- -

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;