1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGA

Variant names:

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

Variant summary

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

The NM_000143.4(FH):​c.1237-16_1237-13delTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00503 in 1,486,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0052 (0 hom.)
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• 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-TGAGA-T is Benign according to our data. Variant chr1-241500602-TGAGA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296872.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr1-241500602-TGAGA-T is described in Lovd as [Likely_benign]. Variant chr1-241500602-TGAGA-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00354 (474/133868) while in subpopulation EAS AF= 0.0104 (48/4598). AF 95% confidence interval is 0.00809. There are 0 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 474 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 473 AN: 133780 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00594

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00532

Gnomad ASJ AF: 0.00183

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.00566

Gnomad FIN AF: 0.000141

Gnomad MID AF: 0.0139

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00393

GnomAD4 exome AF: 0.00518 AC: 7002 AN: 1352738 Hom.: 0 AF XY: 0.00518 AC XY: 3490 AN XY: 673448

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.00596

Gnomad4 EAS exome AF: 0.0141

Gnomad4 SAS exome AF: 0.00725

Gnomad4 FIN exome AF: 0.00402

Gnomad4 NFE exome AF: 0.00373

Gnomad4 OTH exome AF: 0.00629

GnomAD4 genome AF: 0.00354 AC: 474 AN: 133868 Hom.: 0 Cov.: 0 AF XY: 0.00349 AC XY: 223 AN XY: 63850

Gnomad4 AFR AF: 0.00595

Gnomad4 AMR AF: 0.00532

Gnomad4 ASJ AF: 0.00183

Gnomad4 EAS AF: 0.0104

Gnomad4 SAS AF: 0.00567

Gnomad4 FIN AF: 0.000141

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.00389

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

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

- -

Fumarase deficiency Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified 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

- -

Hereditary cancer-predisposing syndrome Benign:1

Jun 25, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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;