rs3744903

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001281740.3(FHOD3):​c.3477C>T​(p.Asn1159Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,613,170 control chromosomes in the GnomAD database, including 94,866 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7308 hom., cov: 32)
Exomes 𝑓: 0.34 ( 87558 hom. )

Consequence

FHOD3
NM_001281740.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.500
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 Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
Variant 18-36730705-C-T is Benign according to our data. Variant chr18-36730705-C-T is described in ClinVar as [Benign]. Clinvar id is 1239394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.5 with no splicing effect.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FHOD3NM_001281740.3 linkuse as main transcriptc.3477C>T p.Asn1159Asn synonymous_variant 20/29 ENST00000590592.6 NP_001268669.1 Q2V2M9-4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FHOD3ENST00000590592.6 linkuse as main transcriptc.3477C>T p.Asn1159Asn synonymous_variant 20/291 NM_001281740.3 ENSP00000466937.1 Q2V2M9-4

Frequencies

GnomAD3 genomes
AF:
0.299
AC:
45490
AN:
151946
Hom.:
7298
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.183
Gnomad AMI
AF:
0.346
Gnomad AMR
AF:
0.406
Gnomad ASJ
AF:
0.298
Gnomad EAS
AF:
0.309
Gnomad SAS
AF:
0.446
Gnomad FIN
AF:
0.275
Gnomad MID
AF:
0.358
Gnomad NFE
AF:
0.337
Gnomad OTH
AF:
0.328
GnomAD3 exomes
AF:
0.350
AC:
87893
AN:
251090
Hom.:
16432
AF XY:
0.353
AC XY:
47939
AN XY:
135714
show subpopulations
Gnomad AFR exome
AF:
0.183
Gnomad AMR exome
AF:
0.491
Gnomad ASJ exome
AF:
0.307
Gnomad EAS exome
AF:
0.295
Gnomad SAS exome
AF:
0.453
Gnomad FIN exome
AF:
0.279
Gnomad NFE exome
AF:
0.330
Gnomad OTH exome
AF:
0.353
GnomAD4 exome
AF:
0.342
AC:
499219
AN:
1461106
Hom.:
87558
Cov.:
35
AF XY:
0.345
AC XY:
250445
AN XY:
726866
show subpopulations
Gnomad4 AFR exome
AF:
0.177
Gnomad4 AMR exome
AF:
0.484
Gnomad4 ASJ exome
AF:
0.304
Gnomad4 EAS exome
AF:
0.299
Gnomad4 SAS exome
AF:
0.448
Gnomad4 FIN exome
AF:
0.276
Gnomad4 NFE exome
AF:
0.338
Gnomad4 OTH exome
AF:
0.338
GnomAD4 genome
AF:
0.299
AC:
45510
AN:
152064
Hom.:
7308
Cov.:
32
AF XY:
0.302
AC XY:
22426
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.183
Gnomad4 AMR
AF:
0.406
Gnomad4 ASJ
AF:
0.298
Gnomad4 EAS
AF:
0.309
Gnomad4 SAS
AF:
0.446
Gnomad4 FIN
AF:
0.275
Gnomad4 NFE
AF:
0.337
Gnomad4 OTH
AF:
0.328
Alfa
AF:
0.331
Hom.:
11668
Bravo
AF:
0.299
Asia WGS
AF:
0.379
AC:
1318
AN:
3478
EpiCase
AF:
0.344
EpiControl
AF:
0.345

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxSep 06, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.43
CADD
Benign
2.5
DANN
Benign
0.68

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

LitVar

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

Other links and lift over

dbSNP: rs3744903; hg19: chr18-34310668; COSMIC: COSV57166663; API