Variant 18-36297885-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001281740.3(FHOD3):c.50T>C(p.Phe17Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FHOD3
NM_001281740.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.29

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3 link	c.50T>C	p.Phe17Ser	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.50T>C	p.Phe17Ser	missense_variant	Exon 1 of 29	1	NM_001281740.3	ENSP00000466937.1	Q2V2M9-4
FHOD3	ENST00000257209.8 link	c.50T>C	p.Phe17Ser	missense_variant	Exon 1 of 25	1		ENSP00000257209.3	Q2V2M9-3
FHOD3	ENST00000359247.8 link	c.50T>C	p.Phe17Ser	missense_variant	Exon 1 of 24	1		ENSP00000352186.3	Q2V2M9-1
FHOD3	ENST00000589114.5 link	n.169T>C		non_coding_transcript_exon_variant	Exon 1 of 14	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1405948

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695050

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

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

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.50T>C (p.F17S) alteration is located in exon 1 (coding exon 1) of the FHOD3 gene. This alteration results from a T to C substitution at nucleotide position 50, causing the phenylalanine (F) at amino acid position 17 to be replaced by a serine (S). 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

0.99

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

.;.;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.89

D;T;D

M_CAP

Pathogenic

0.67

MetaRNN

Uncertain

0.65

D;D;D

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-5.0

D;.;D

REVEL

Benign

0.24

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.92

P;.;D

Vest4

0.53

MutPred

0.52

Gain of relative solvent accessibility (P = 0.0104);Gain of relative solvent accessibility (P = 0.0104);Gain of relative solvent accessibility (P = 0.0104);

MVP

0.14

MPC

3.5

ClinPred

1.0

GERP RS

3.7

Varity_R

0.88

gMVP

0.69

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over