1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1

The NM_000143.4(FH):​c.1237-14_1237-13dupTC 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 0.10 ( 702 hom., cov: 0)
Exomes 𝑓: 0.16 ( 62 hom. )
Failed GnomAD Quality Control

Consequence

FH
NM_000143.4 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: -0.993
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6
Variant 1-241500602-T-TGA is Benign according to our data. Variant chr1-241500602-T-TGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296865.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=4, Likely_benign=1}.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FHNM_000143.4 linkc.1237-14_1237-13dupTC intron_variant Intron 8 of 9 ENST00000366560.4 NP_000134.2 P07954-1A0A0S2Z4C3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FHENST00000366560.4 linkc.1237-14_1237-13dupTC intron_variant Intron 8 of 9 1 NM_000143.4 ENSP00000355518.4 P07954-1

Frequencies

GnomAD3 genomes
AF:
0.100
AC:
13380
AN:
133644
Hom.:
702
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.0600
Gnomad AMI
AF:
0.154
Gnomad AMR
AF:
0.0775
Gnomad ASJ
AF:
0.0991
Gnomad EAS
AF:
0.106
Gnomad SAS
AF:
0.0591
Gnomad FIN
AF:
0.161
Gnomad MID
AF:
0.108
Gnomad NFE
AF:
0.122
Gnomad OTH
AF:
0.0840
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.157
AC:
209116
AN:
1328574
Hom.:
62
Cov.:
48
AF XY:
0.158
AC XY:
104355
AN XY:
661282
show subpopulations
Gnomad4 AFR exome
AF:
0.0739
Gnomad4 AMR exome
AF:
0.134
Gnomad4 ASJ exome
AF:
0.144
Gnomad4 EAS exome
AF:
0.112
Gnomad4 SAS exome
AF:
0.155
Gnomad4 FIN exome
AF:
0.172
Gnomad4 NFE exome
AF:
0.163
Gnomad4 OTH exome
AF:
0.148
GnomAD4 genome
AF:
0.100
AC:
13381
AN:
133730
Hom.:
702
Cov.:
0
AF XY:
0.101
AC XY:
6462
AN XY:
63792
show subpopulations
Gnomad4 AFR
AF:
0.0599
Gnomad4 AMR
AF:
0.0773
Gnomad4 ASJ
AF:
0.0991
Gnomad4 EAS
AF:
0.106
Gnomad4 SAS
AF:
0.0593
Gnomad4 FIN
AF:
0.161
Gnomad4 NFE
AF:
0.122
Gnomad4 OTH
AF:
0.0848

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:3
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

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: See variant below -

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

- -

Fumarase deficiency Uncertain:1Benign:1
May 28, 2019
Mendelics
Significance: 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

- -

Hereditary cancer-predisposing syndrome Benign:2
Jun 07, 2021
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Dec 18, 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. -

not provided Benign:1
Aug 09, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144131869; hg19: chr1-241663902; API