1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

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. 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 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

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

hereditary leiomyomatosis and renal cell cancer
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
fumaric aciduria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
pheochromocytoma-paraganglioma
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
leiomyosarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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 VariationId is 296870.

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 passed quality control check.

BS2

High Homozygotes in GnomAd4 at 36 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000143.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	NM_000143.4	MANE Select	c.1237-24_1237-13dupTCTCTCTCTCTC		intron	N/A	NP_000134.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FH	ENST00000366560.4	TSL:1 MANE Select	c.1237-24_1237-13dupTCTCTCTCTCTC	intron	N/A	ENSP00000355518.4
FH	ENST00000682567.1		n.4613_4624dupTCTCTCTCTCTC	non_coding_transcript_exon	Exon 7 of 8
FH	ENST00000683521.1		c.1237-24_1237-13dupTCTCTCTCTCTC	intron	N/A	ENSP00000506864.1

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

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

African (AFR)

AF:

0.0213

AC:

658

AN:

30944

American (AMR)

AF:

0.00976

AC:

402

AN:

41186

Ashkenazi Jewish (ASJ)

AF:

0.00871

AC:

212

AN:

24338

East Asian (EAS)

AF:

0.0105

AC:

395

AN:

37446

South Asian (SAS)

AF:

0.0110

AC:

881

AN:

80244

European-Finnish (FIN)

AF:

0.0193

AC:

754

AN:

39084

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

4180

European-Non Finnish (NFE)

AF:

0.0258

AC:

26561

AN:

1027676

Other (OTH)

AF:

0.0219

AC:

1220

AN:

55590

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.340

Heterozygous variant carriers

1712

3424

5136

6848

8560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.0264

AC:

921

AN:

34900

American (AMR)

AF:

0.0161

AC:

212

AN:

13160

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3274

East Asian (EAS)

AF:

0.0309

AC:

142

AN:

4596

South Asian (SAS)

AF:

0.0168

AC:

AN:

4048

European-Finnish (FIN)

AF:

0.00592

AC:

AN:

7092

Middle Eastern (MID)

AF:

0.00746

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.0192

AC:

1226

AN:

63754

Other (OTH)

AF:

0.0184

AC:

AN:

1794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

109

219

328

438

547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

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

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

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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 v4.9

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over