chr18-36527489-T-C

Position:

• chr18-36527489-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.511+14946T>C		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+14946T>C		intron_variant		1	NM_001281740.3	ENSP00000466937.1
FHOD3	ENST00000257209.8	c.511+14946T>C		intron_variant		1		ENSP00000257209.3
FHOD3	ENST00000359247.8	c.511+14946T>C		intron_variant		1		ENSP00000352186.3
FHOD3	ENST00000589114.5	n.630+14946T>C		intron_variant		2

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

Gnomad4 AFR AF: 0.0305

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.0504

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.0387

Gnomad4 NFE AF: 0.0699

Gnomad4 OTH AF: 0.0686

Alfa AF: 0.0663 Hom.: 426

Bravo AF: 0.0702

Asia WGS AF: 0.128 AC: 447 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.4
DANN	Benign	0.38

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: rs17651157; hg19: chr18-34107452;