chr18-36355570-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001281740.3(FHOD3):ā€‹c.197A>Gā€‹(p.Asn66Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,614,010 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 (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000028 ( 0 hom. )

Consequence

FHOD3
NM_001281740.3 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.32
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 Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10569158).
BS2
High AC in GnomAdExome4 at 41 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FHOD3NM_001281740.3 linkuse as main transcriptc.197A>G p.Asn66Ser missense_variant 2/29 ENST00000590592.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FHOD3ENST00000590592.6 linkuse as main transcriptc.197A>G p.Asn66Ser missense_variant 2/291 NM_001281740.3 A2Q2V2M9-4
FHOD3ENST00000257209.8 linkuse as main transcriptc.197A>G p.Asn66Ser missense_variant 2/251 P4Q2V2M9-3
FHOD3ENST00000359247.8 linkuse as main transcriptc.197A>G p.Asn66Ser missense_variant 2/241 A2Q2V2M9-1
FHOD3ENST00000589114.5 linkuse as main transcriptn.316A>G non_coding_transcript_exon_variant 2/142

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152172
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000289
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000676
AC:
17
AN:
251402
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00129
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000280
AC:
41
AN:
1461838
Hom.:
0
Cov.:
30
AF XY:
0.0000261
AC XY:
19
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00107
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152172
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000289
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000115
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.019
.;.;T
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.87
D;D;D
M_CAP
Benign
0.0082
T
MetaRNN
Benign
0.11
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
L;L;L
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-2.2
N;.;N
REVEL
Benign
0.087
Sift
Benign
0.55
T;.;T
Sift4G
Benign
0.49
T;T;T
Polyphen
1.0
D;.;D
Vest4
0.43
MVP
0.22
MPC
0.59
ClinPred
0.60
D
GERP RS
6.1
Varity_R
0.099
gMVP
0.068

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs375600648; hg19: chr18-33935533; API