18-36297905-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001281740.3(FHOD3):c.70G>A(p.Glu24Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000711 in 1,406,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

FHOD3
NM_001281740.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.12

Publications

0 publications found

Variant links:

Genes affected

FHOD3 (HGNC:26178): (formin homology 2 domain containing 3) The protein encoded by this gene is a member of the diaphanous-related formins (DRF), and contains multiple domains, including GBD (GTPase-binding domain), DID (diaphanous inhibitory domain), FH1 (formin homology 1), FH2 (formin homology 2), and DAD (diaphanous auto-regulatory domain) domains. This protein is thought to play a role in actin filament polymerization in cardiomyocytes. Mutations in this gene have been associated with dilated cardiomyopathy (DCM), characterized by dilation of the ventricular chamber, leading to impairment of systolic pump function and subsequent heart failure. Increased levels of the protein encoded by this gene have been observed in individuals with hypertrophic cardiomyopathy (HCM). Alternative splicing results in multiple transcript variants encoding different isoforms. A muscle-specific isoform has been shown to possess a casein kinase 2 (CK2) phosphorylation site at the C-terminal end of the FH2 domain. Phosphorylation of this site alters its interaction with sequestosome 1 (SQSTM1), and targets this isoform to myofibrils, while other isoforms form cytoplasmic aggregates. [provided by RefSeq, Aug 2015]

FHOD3 Gene-Disease associations (from GenCC):

cardiomyopathy, familial hypertrophic, 28
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: MODERATE Submitted by: Illumina

FHOD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37097532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3 link	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 29	ENST00000590592.6	NP_001268669.1	Q2V2M9-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FHOD3	ENST00000590592.6 link	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 29	1	NM_001281740.3	ENSP00000466937.1	Q2V2M9-4
FHOD3	ENST00000257209.8 link	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 25	1		ENSP00000257209.3	Q2V2M9-3
FHOD3	ENST00000359247.8 link	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 24	1		ENSP00000352186.3	Q2V2M9-1
FHOD3	ENST00000589114.5 link	n.189G>A		non_coding_transcript_exon_variant	Exon 1 of 14	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1406652

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695466

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30882

American (AMR)

AF:

0.00

AC:

AN:

37484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25054

East Asian (EAS)

AF:

0.00

AC:

AN:

35776

South Asian (SAS)

AF:

0.00

AC:

AN:

79456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49120

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1084952

Other (OTH)

AF:

0.00

AC:

AN:

58240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 18, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.70G>A (p.E24K) alteration is located in exon 1 (coding exon 1) of the FHOD3 gene. This alteration results from a G to A substitution at nucleotide position 70, causing the glutamic acid (E) at amino acid position 24 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

.;.;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.37

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.6

M;M;M

PhyloP100

7.1

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-2.4

N;.;N

REVEL

Benign

0.20

Sift

Benign

0.037

D;.;D

Sift4G

Uncertain

0.030

D;D;D

Polyphen

1.0

D;.;P

Vest4

0.34

MutPred

0.27

Gain of methylation at E24 (P = 0.0067);Gain of methylation at E24 (P = 0.0067);Gain of methylation at E24 (P = 0.0067);

MVP

0.13

MPC

2.6

ClinPred

0.99

GERP RS

3.2

PromoterAI

0.068

Neutral

(source)

Varity_R

0.30

gMVP

0.65

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

18-36297905-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over