NM_000143.4:c.1237-20_1237-13delTCTCTCTC

Variant names:

Variant summary

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

The NM_000143.4(FH):c.1237-20_1237-13delTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,490,680 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0044 ( 7 hom., cov: 0)

Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

FH
NM_000143.4 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B: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 -9 ACMG points.

BP6

Variant 1-241500602-TGAGAGAGA-T is Benign according to our data. Variant chr1-241500602-TGAGAGAGA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1336271.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00437 (585/133894) while in subpopulation AFR AF = 0.0154 (539/34966). AF 95% confidence interval is 0.0143. There are 7 homozygotes in GnomAd4. There are 241 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 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.1237-20_1237-13delTCTCTCTC		intron	N/A	NP_000134.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FH	ENST00000366560.4	TSL:1 MANE Select	c.1237-20_1237-13delTCTCTCTC	intron	N/A	ENSP00000355518.4
FH	ENST00000682567.1		n.4617_4624delTCTCTCTC	non_coding_transcript_exon	Exon 7 of 8
FH	ENST00000683521.1		c.1237-20_1237-13delTCTCTCTC	intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes

AF:

0.00436

AC:

584

AN:

133804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00160

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000434

Gnomad SAS

AF:

0.000984

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000157

Gnomad OTH

AF:

0.00506

GnomAD4 exome

AF:

0.000753

AC:

1021

AN:

1356786

Hom.:

AF XY:

0.000731

AC XY:

494

AN XY:

675456

show subpopulations

African (AFR)

AF:

0.0138

AC:

433

AN:

31296

American (AMR)

AF:

0.00135

AC:

AN:

41448

Ashkenazi Jewish (ASJ)

AF:

0.0000818

AC:

AN:

24456

East Asian (EAS)

AF:

0.000212

AC:

AN:

37714

South Asian (SAS)

AF:

0.00158

AC:

128

AN:

80762

European-Finnish (FIN)

AF:

0.000101

AC:

AN:

39766

Middle Eastern (MID)

AF:

0.000951

AC:

AN:

4204

European-Non Finnish (NFE)

AF:

0.000295

AC:

307

AN:

1040844

Other (OTH)

AF:

0.00140

AC:

AN:

56296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.00437

AC:

585

AN:

133894

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

241

AN XY:

63870

show subpopulations

African (AFR)

AF:

0.0154

AC:

539

AN:

34966

American (AMR)

AF:

0.00159

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:

0.000987

AC:

AN:

4054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.000157

AC:

AN:

63794

Other (OTH)

AF:

0.00501

AC:

AN:

1798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.552

Heterozygous variant carriers

109

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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Dec 20, 2019

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the FH gene demonstrated a sequence change in intron 8, c.1237-20_1237-13del. This change does not appear to have been previously described in patients with FH-related disorders and has also not been described in population databases (gnomAD, ExAC). This sequence change is not clearly predicted to have a deleterious effect on splicing based on in silico splice prediction programs. It is possible that this sequence change represents a benign sequence change in the FH gene that has not been identified to date. The functional significance of this sequence change is not known at present and its contribution to the disease phenotype cannot definitively be determined.

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

Jan 04, 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

Mar 27, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

FH-related disorder

Benign:1

Oct 05, 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 v4.9

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