1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1

The NM_000143.4(FH):c.1237-18_1237-13delTCTCTC variant causes a 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 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.18

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 -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 VariationId is 1336415.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 = 0.00125 (167/133890) while in subpopulation AFR AF = 0.00323 (113/34962). AF 95% confidence interval is 0.00275. There are 1 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.1237-18_1237-13delTCTCTC		intron	N/A	NP_000134.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FH	ENST00000366560.4	TSL:1 MANE Select	c.1237-18_1237-13delTCTCTC	intron	N/A	ENSP00000355518.4
FH	ENST00000682567.1		n.4619_4624delTCTCTC	non_coding_transcript_exon	Exon 7 of 8
FH	ENST00000683521.1		c.1237-18_1237-13delTCTCTC	intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

165

AN:

133802

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00101

AC XY:

684

AN XY:

675224

show subpopulations

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

African (AFR)

AF:

0.00422

AC:

132

AN:

31266

American (AMR)

AF:

0.00295

AC:

122

AN:

41420

Ashkenazi Jewish (ASJ)

AF:

0.000286

AC:

AN:

24452

East Asian (EAS)

AF:

0.00191

AC:

AN:

37676

South Asian (SAS)

AF:

0.000966

AC:

AN:

80730

European-Finnish (FIN)

AF:

0.000453

AC:

AN:

39748

Middle Eastern (MID)

AF:

0.00167

AC:

AN:

4204

European-Non Finnish (NFE)

AF:

0.000799

AC:

831

AN:

1040594

Other (OTH)

AF:

0.00128

AC:

AN:

56282

⚠️ 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: 0.368

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00125

AC:

167

AN:

133890

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

63868

show subpopulations

African (AFR)

AF:

0.00323

AC:

113

AN:

34962

American (AMR)

AF:

0.000228

AC:

AN:

13172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3274

East Asian (EAS)

AF:

0.000435

AC:

AN:

4600

South Asian (SAS)

AF:

0.000247

AC:

AN:

4054

European-Finnish (FIN)

AF:

0.000141

AC:

AN:

7100

Middle Eastern (MID)

AF:

0.00741

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.000658

AC:

AN:

63794

Other (OTH)

AF:

0.00167

AC:

AN:

1798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 11, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary leiomyomatosis and renal cell cancer

Benign:1

Dec 06, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:1

Feb 23, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.2

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