rs17651157

Variant names:

• chr18-36527489-T-C
• rs17651157
• NM_001281740.3:c.511+14946T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001281740.3(FHOD3):​c.511+14946T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0679 in 152,294 control chromosomes in the GnomAD database, including 560 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.068 (560 hom., cov: 32)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.241
• Publications: 8 publications found

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):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, ClinGen
• cardiomyopathy, familial hypertrophic, 28

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001281740.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHOD3	NM_001281740.3	MANE Select	c.511+14946T>C		intron	N/A	NP_001268669.1	Q2V2M9-4
	FHOD3	NM_025135.5		c.511+14946T>C		intron	N/A	NP_079411.2
	FHOD3	NM_001281739.3		c.511+14946T>C		intron	N/A	NP_001268668.1	Q2V2M9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHOD3	ENST00000590592.6	TSL:1 MANE Select	c.511+14946T>C		intron	N/A	ENSP00000466937.1	Q2V2M9-4
	FHOD3	ENST00000257209.8	TSL:1	c.511+14946T>C		intron	N/A	ENSP00000257209.3	Q2V2M9-3
	FHOD3	ENST00000359247.8	TSL:1	c.511+14946T>C		intron	N/A	ENSP00000352186.3	Q2V2M9-1

Frequencies

GnomAD3 genomes AF: 0.0679 AC: 10338 AN: 152176 Hom.: 560 Cov.: 32

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.0501

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0699

Gnomad OTH AF: 0.0664

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0679 AC: 10344 AN: 152294 Hom.: 560 Cov.: 32 AF XY: 0.0704 AC XY: 5240 AN XY: 74462

African (AFR) AF: 0.0305 AC: 1268 AN: 41558

American (AMR) AF: 0.145 AC: 2213 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3470

East Asian (EAS) AF: 0.0504 AC: 261 AN: 5180

South Asian (SAS) AF: 0.223 AC: 1076 AN: 4822

European-Finnish (FIN) AF: 0.0387 AC: 411 AN: 10620

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0699 AC: 4758 AN: 68028

Other (OTH) AF: 0.0686 AC: 145 AN: 2114

Alfa AF: 0.0680 Hom.: 1280

Bravo AF: 0.0702

Asia WGS AF: 0.128 AC: 447 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.4
DANN	Benign	0.38
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17651157; hg19: chr18-34107452;