1-241500602-T-TGAGAGAGAGAGAGAGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000143.4(FH):c.1237-28_1237-13dupTCTCTCTCTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 12 hom., cov: 0)

Exomes 𝑓: 0.0033 ( 11 hom. )

Failed GnomAD Quality Control

Consequence

FH
NM_000143.4 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

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 -16 ACMG points.

BP6

Variant 1-241500602-T-TGAGAGAGAGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGAGAGAGAGA is described in ClinVar as [Likely_benign]. Clinvar id is 1692238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00884 (1183/133790) while in subpopulation AFR AF = 0.0175 (610/34908). AF 95% confidence interval is 0.0163. There are 12 homozygotes in GnomAd4. There are 535 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4 link	c.1237-28_1237-13dupTCTCTCTCTCTCTCTC		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.1237-28_1237-13dupTCTCTCTCTCTCTCTC		intron_variant	Intron 8 of 9	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

AF:

0.00886

AC:

1184

AN:

133700

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0175

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00441

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00130

Gnomad SAS

AF:

0.000984

Gnomad FIN

AF:

0.00183

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00707

Gnomad OTH

AF:

0.00507

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00329

AC:

4449

AN:

1353852

Hom.:

Cov.:

AF XY:

0.00327

AC XY:

2207

AN XY:

673992

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00796

AC:

248

AN:

31166

American (AMR)

AF:

0.00152

AC:

AN:

41390

Ashkenazi Jewish (ASJ)

AF:

0.00620

AC:

151

AN:

24350

East Asian (EAS)

AF:

0.000345

AC:

AN:

37692

South Asian (SAS)

AF:

0.00105

AC:

AN:

80696

European-Finnish (FIN)

AF:

0.00368

AC:

146

AN:

39630

Middle Eastern (MID)

AF:

0.00262

AC:

AN:

4194

European-Non Finnish (NFE)

AF:

0.00340

AC:

3526

AN:

1038570

Other (OTH)

AF:

0.00367

AC:

206

AN:

56164

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.331

Heterozygous variant carriers

259

518

777

1036

1295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00884

AC:

1183

AN:

133790

Hom.:

Cov.:

AF XY:

0.00838

AC XY:

535

AN XY:

63812

show subpopulations

African (AFR)

AF:

0.0175

AC:

610

AN:

34908

American (AMR)

AF:

0.00433

AC:

AN:

13170

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3272

East Asian (EAS)

AF:

0.00130

AC:

AN:

4598

South Asian (SAS)

AF:

0.000987

AC:

AN:

4054

European-Finnish (FIN)

AF:

0.00183

AC:

AN:

7094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.00707

AC:

451

AN:

63766

Other (OTH)

AF:

0.00502

AC:

AN:

1794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

101

151

202

252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

226

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 leiomyomatosis and renal cell cancer

Benign:1

Sep 08, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer

Benign:1

Jul 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Mar 01, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

FH-related disorder

Benign:1

Aug 04, 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

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.99

Mutation Taster

=100/0

polymorphism

(source)

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 for variant 1:241500602 T>TGAGAGAGAGAGAGAGA . It may be empty.

1-241500602-T-TGAGAGAGAGAGAGAGA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over