1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000143.4(FH):​c.1237-20_1237-13delTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,490,680 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0044 ( 7 hom., cov: 0)
Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

FH
NM_000143.4 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.18
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-TGAGAGAGA-T is Benign according to our data. Variant chr1-241500602-TGAGAGAGA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1336271.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr1-241500602-TGAGAGAGA-T is described in Lovd as [Likely_benign]. Variant chr1-241500602-TGAGAGAGA-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00437 (585/133894) while in subpopulation AFR AF= 0.0154 (539/34966). AF 95% confidence interval is 0.0143. There are 7 homozygotes in gnomad4. There are 241 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
BS2
High AC in GnomAd4 at 585 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FHNM_000143.4 linkc.1237-20_1237-13delTCTCTCTC 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.1237-20_1237-13delTCTCTCTC intron_variant Intron 8 of 9 1 NM_000143.4 ENSP00000355518.4 P07954-1

Frequencies

GnomAD3 genomes
AF:
0.00436
AC:
584
AN:
133804
Hom.:
7
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.0154
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00160
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000434
Gnomad SAS
AF:
0.000984
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000157
Gnomad OTH
AF:
0.00506
GnomAD4 exome
AF:
0.000753
AC:
1021
AN:
1356786
Hom.:
0
AF XY:
0.000731
AC XY:
494
AN XY:
675456
show subpopulations
Gnomad4 AFR exome
AF:
0.0138
Gnomad4 AMR exome
AF:
0.00135
Gnomad4 ASJ exome
AF:
0.0000818
Gnomad4 EAS exome
AF:
0.000212
Gnomad4 SAS exome
AF:
0.00158
Gnomad4 FIN exome
AF:
0.000101
Gnomad4 NFE exome
AF:
0.000295
Gnomad4 OTH exome
AF:
0.00140
GnomAD4 genome
AF:
0.00437
AC:
585
AN:
133894
Hom.:
7
Cov.:
0
AF XY:
0.00377
AC XY:
241
AN XY:
63870
show subpopulations
Gnomad4 AFR
AF:
0.0154
Gnomad4 AMR
AF:
0.00159
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000435
Gnomad4 SAS
AF:
0.000987
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000157
Gnomad4 OTH
AF:
0.00501

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:1
Dec 20, 2019
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

DNA sequence analysis of the FH gene demonstrated a sequence change in intron 8, c.1237-20_1237-13del. This change does not appear to have been previously described in patients with FH-related disorders and has also not been described in population databases (gnomAD, ExAC). This sequence change is not clearly predicted to have a deleterious effect on splicing based on in silico splice prediction programs. It is possible that this sequence change represents a benign sequence change in the FH gene that has not been identified to date. The functional significance of this sequence change is not known at present and its contribution to the disease phenotype cannot definitively be determined. -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1
Mar 27, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

FH-related disorder Benign:1
Oct 05, 2021
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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