1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGA

Variant names:

• chr1-241500602-T-TGAGA
• rs144131869
• NM_000143.4:c.1237-16_1237-13dupTCTC

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000143.4(FH):​c.1237-16_1237-13dupTCTC variant causes a 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 0.26 (4472 hom., cov: 0)
  • Exomes 𝑓: 0.24 (433 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 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 Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 1-241500602-T-TGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296866.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=1, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4	c.1237-16_1237-13dupTCTC		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.1237-16_1237-13dupTCTC		intron_variant	Intron 8 of 9	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 34085 AN: 133608 Hom.: 4472 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.292

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.272

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.239 AC: 315854 AN: 1321580 Hom.: 433 Cov.: 48 AF XY: 0.240 AC XY: 157560 AN XY: 657174

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.159

Gnomad4 SAS exome AF: 0.275

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.245

Gnomad4 OTH exome AF: 0.228

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.255 AC: 34101 AN: 133698 Hom.: 4472 Cov.: 0 AF XY: 0.256 AC XY: 16320 AN XY: 63768

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.317

Gnomad4 ASJ AF: 0.276

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.276

Gnomad4 NFE AF: 0.293

Gnomad4 OTH AF: 0.272

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary leiomyomatosis and renal cell cancer Uncertain:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Expansion of intronic repeat, unlikely to impact splicing. Other expansions near this position (maybe same one? Hard to tell) present in ExAC at moderate frequency (~0.1% E. Asian) -

Sep 03, 2021

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Fumarase deficiency Uncertain:1 Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Aug 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Dec 16, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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;