rs10502661

Positions:

• chr18-36540192-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001281740.3(FHOD3):​c.511+27649C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0658 in 152,228 control chromosomes in the GnomAD database, including 526 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 0.066 (526 hom., cov: 32)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.363

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.511+27649C>T		intron_variant		ENST00000590592.6	NP_001268669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHOD3	ENST00000590592.6	c.511+27649C>T		intron_variant		1	NM_001281740.3	ENSP00000466937	A2
FHOD3	ENST00000257209.8	c.511+27649C>T		intron_variant		1		ENSP00000257209	P4
FHOD3	ENST00000359247.8	c.511+27649C>T		intron_variant		1		ENSP00000352186	A2
FHOD3	ENST00000589114.5	n.630+27649C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0658 AC: 10006 AN: 152110 Hom.: 526 Cov.: 32

Gnomad AFR AF: 0.0289

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.0508

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.0425

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0682

Gnomad OTH AF: 0.0541

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

GnomAD4 genome AF: 0.0658 AC: 10010 AN: 152228 Hom.: 526 Cov.: 32 AF XY: 0.0686 AC XY: 5106 AN XY: 74434

Gnomad4 AFR AF: 0.0289

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.0511

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.0425

Gnomad4 NFE AF: 0.0682

Gnomad4 OTH AF: 0.0559

Alfa AF: 0.0781 Hom.: 120

Bravo AF: 0.0671

Asia WGS AF: 0.120 AC: 416 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.60

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

Other links and lift over

dbSNP: rs10502661; hg19: chr18-34120155;