1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGA

Variant names:

• chr1-241500602-TGAGAGAGA-T
• rs144131869
• NM_000143.4:c.1237-20_1237-13delTCTCTCTC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.18

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 -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: {Likely_benign=2, Uncertain_significance=1}. 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
FH	NM_000143.4	c.1237-20_1237-13delTCTCTCTC		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.1237-20_1237-13delTCTCTCTC		intron_variant	Intron 8 of 9	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes AF: 0.00436 AC: 584 AN: 133804 Hom.: 7 Cov.: 0

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

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

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:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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

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;