chr1-241500602-T-TGAGAGAGAGAGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000143.4(FH):c.1237-24_1237-13dupTCTCTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.020 ( 36 hom., cov: 0)

Exomes 𝑓: 0.023 ( 155 hom. )

Failed GnomAD Quality Control

Consequence

FH
NM_000143.4 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: -0.993

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 was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 1-241500602-T-TGAGAGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGAGAGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296870.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3, Benign=1}.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0201 (2695/133752) while in subpopulation EAS AF = 0.0309 (142/4596). AF 95% confidence interval is 0.0268. There are 36 homozygotes in GnomAd4. There are 1234 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 2695 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4 link	c.1237-24_1237-13dupTCTCTCTCTCTC		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.1237-24_1237-13dupTCTCTCTCTCTC		intron_variant	Intron 8 of 9	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

AF:

0.0201

AC:

2691

AN:

133662

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0264

Gnomad AMI

AF:

0.00346

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.0308

Gnomad SAS

AF:

0.0167

Gnomad FIN

AF:

0.00592

Gnomad MID

AF:

0.0105

Gnomad NFE

AF:

0.0192

Gnomad OTH

AF:

0.0186

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0232

AC:

31148

AN:

1340688

Hom.:

155

Cov.:

AF XY:

0.0228

AC XY:

15225

AN XY:

667398

show subpopulations

Gnomad4 AFR exome

AF:

0.0213

AC:

658

AN:

30944

Gnomad4 AMR exome

AF:

0.00976

AC:

402

AN:

41186

Gnomad4 ASJ exome

AF:

0.00871

AC:

212

AN:

24338

Gnomad4 EAS exome

AF:

0.0105

AC:

395

AN:

37446

Gnomad4 SAS exome

AF:

0.0110

AC:

881

AN:

80244

Gnomad4 FIN exome

AF:

0.0193

AC:

754

AN:

39084

Gnomad4 NFE exome

AF:

0.0258

AC:

26561

AN:

1027676

Gnomad4 Remaining exome

AF:

0.0219

AC:

1220

AN:

55590

Heterozygous variant carriers

1712

3424

5136

6848

8560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

1026

2052

3078

4104

5130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0201

AC:

2695

AN:

133752

Hom.:

Cov.:

AF XY:

0.0193

AC XY:

1234

AN XY:

63774

show subpopulations

Gnomad4 AFR

AF:

0.0264

AC:

0.0263897

AN:

0.0263897

Gnomad4 AMR

AF:

0.0161

AC:

0.0161094

AN:

0.0161094

Gnomad4 ASJ

AF:

0.0141

AC:

0.0140501

AN:

0.0140501

Gnomad4 EAS

AF:

0.0309

AC:

0.0308964

AN:

0.0308964

Gnomad4 SAS

AF:

0.0168

AC:

0.0167984

AN:

0.0167984

Gnomad4 FIN

AF:

0.00592

AC:

0.00592217

AN:

0.00592217

Gnomad4 NFE

AF:

0.0192

AC:

0.0192302

AN:

0.0192302

Gnomad4 OTH

AF:

0.0184

AC:

0.0183946

AN:

0.0183946

Heterozygous variant carriers

109

219

328

438

547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

226

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary leiomyomatosis and renal cell cancer

Uncertain:2Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely benign

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

- -

Nov 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

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

Mar 05, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

FH-related disorder

Benign:1

May 09, 2023

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

Mutation Taster

=100/0

polymorphism

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.

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