Variant 1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGA details in Genebe, Genetics Data Aggregator

Variant summary

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

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

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]

FH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Uncertain_significance=3, Likely_benign=2}. 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 link	c.1237-16_1237-13delTCTC		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
FH	ENST00000366560.4 link	c.1237-16_1237-13delTCTC		intron_variant	Intron 8 of 9	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

AF:

0.00354

AC:

473

AN:

133780

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00518

AC XY:

3490

AN XY:

673448

show subpopulations

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.:

Cov.:

AF XY:

0.00349

AC XY:

223

AN XY:

63850

show subpopulations

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:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

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

Name

Calibrated prediction

Score

Prediction

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over