chr18-36297885-T-C

Variant summary

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

The NM_001281740.3(FHOD3):ā€‹c.50T>Cā€‹(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 (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

FHOD3
NM_001281740.3 missense

Scores

6
6
7

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]

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/exons MANE UniProt
FHOD3NM_001281740.3 linkuse as main transcriptc.50T>C p.Phe17Ser missense_variant 1/29 ENST00000590592.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FHOD3ENST00000590592.6 linkuse as main transcriptc.50T>C p.Phe17Ser missense_variant 1/291 NM_001281740.3 A2Q2V2M9-4
FHOD3ENST00000257209.8 linkuse as main transcriptc.50T>C p.Phe17Ser missense_variant 1/251 P4Q2V2M9-3
FHOD3ENST00000359247.8 linkuse as main transcriptc.50T>C p.Phe17Ser missense_variant 1/241 A2Q2V2M9-1
FHOD3ENST00000589114.5 linkuse as main transcriptn.169T>C non_coding_transcript_exon_variant 1/142

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1405948
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
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.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 17, 2024The 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
T
BayesDel_noAF
Benign
-0.30
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
.;.;T
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Benign
0.45
N
LIST_S2
Uncertain
0.89
D;T;D
M_CAP
Pathogenic
0.67
D
MetaRNN
Uncertain
0.65
D;D;D
MetaSVM
Benign
-0.58
T
MutationAssessor
Uncertain
2.6
M;M;M
MutationTaster
Benign
0.99
D;D;D;N
PrimateAI
Pathogenic
0.95
D
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
D
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.

Other links and lift over

hg19: chr18-33877848; API