1-241500593-T-TTGAG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000143.4(FH):c.1237-7_1237-4dupCTCA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,440,600 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000051 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

FH
NM_000143.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.123

Publications

0 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: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 1-241500593-T-TTGAG is Benign according to our data. Variant chr1-241500593-T-TTGAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 413608.

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.1237-7_1237-4dupCTCA		splice_region intron	N/A	NP_000134.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FH	ENST00000366560.4	TSL:1 MANE Select	c.1237-7_1237-4dupCTCA	splice_region intron	N/A	ENSP00000355518.4
FH	ENST00000682567.1		n.4630_4633dupCTCA	non_coding_transcript_exon	Exon 7 of 8
FH	ENST00000683521.1		c.1237-7_1237-4dupCTCA	splice_region intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes

AF:

0.0000511

AC:

AN:

78214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000297

Gnomad SAS

AF:

0.000483

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000269

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000172

AC:

AN:

233054

AF XY:

0.0000316

show subpopulations

Gnomad AFR exome

AF:

0.0000675

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000571

Gnomad FIN exome

AF:

0.0000577

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000206

AC:

AN:

1362310

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

680700

show subpopulations

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

African (AFR)

AF:

0.0000628

AC:

AN:

31848

American (AMR)

AF:

0.0000456

AC:

AN:

43888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25022

East Asian (EAS)

AF:

0.000234

AC:

AN:

38430

South Asian (SAS)

AF:

0.00

AC:

AN:

84086

European-Finnish (FIN)

AF:

0.0000829

AC:

AN:

48276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4854

European-Non Finnish (NFE)

AF:

0.00000874

AC:

AN:

1029478

Other (OTH)

AF:

0.0000354

AC:

AN:

56428

⚠️ 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: 0.277

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000511

AC:

AN:

78290

Hom.:

Cov.:

AF XY:

0.0000535

AC XY:

AN XY:

37354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19784

American (AMR)

AF:

0.000133

AC:

AN:

7528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2280

East Asian (EAS)

AF:

0.000298

AC:

AN:

3358

South Asian (SAS)

AF:

0.000484

AC:

AN:

2066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

176

European-Non Finnish (NFE)

AF:

0.0000269

AC:

AN:

37198

Other (OTH)

AF:

0.00

AC:

AN:

1100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Aug 22, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FH c.1237-7_1237-4dup variant has not been reported in individuals with FH-related conditions in the published literature. The frequency of this variant in the general population, 0.000017 (4/233054 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on FH mRNA splicing yielded inconclusive findings. Based on the available information, we are unable to determine the clinical significance of this variant.

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:1

Sep 22, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.12

Mutation Taster

=96/4

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