1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGA

Position:

• chr1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000143.4(FH):​c.1237-18_1237-13del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,490,262 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00099 (0 hom.)
• Consequence: FH NM_000143.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts 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 -12 ACMG points.

• BP6: Variant 1-241500602-TGAGAGA-T is Benign according to our data. Variant chr1-241500602-TGAGAGA-T is described in ClinVar as [Likely_benign]. Clinvar id is 1336415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241500602-TGAGAGA-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 167 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4	c.1237-18_1237-13del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.1237-18_1237-13del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000143.4	ENSP00000355518	P1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 165 AN: 133802 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000228

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000434

Gnomad SAS AF: 0.000246

Gnomad FIN AF: 0.000141

Gnomad MID AF: 0.00694

Gnomad NFE AF: 0.000658

Gnomad OTH AF: 0.00169

GnomAD4 exome AF: 0.000987 AC: 1339 AN: 1356372 Hom.: 0 AF XY: 0.00101 AC XY: 684 AN XY: 675224

Gnomad4 AFR exome AF: 0.00422

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.000286

Gnomad4 EAS exome AF: 0.00191

Gnomad4 SAS exome AF: 0.000966

Gnomad4 FIN exome AF: 0.000453

Gnomad4 NFE exome AF: 0.000799

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00125 AC: 167 AN: 133890 Hom.: 1 Cov.: 0 AF XY: 0.00128 AC XY: 82 AN XY: 63868

Gnomad4 AFR AF: 0.00323

Gnomad4 AMR AF: 0.000228

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000435

Gnomad4 SAS AF: 0.000247

Gnomad4 FIN AF: 0.000141

Gnomad4 NFE AF: 0.000658

Gnomad4 OTH AF: 0.00167

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 11, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Feb 23, 2021

- -

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;