18-36371033-C-T

Position:

• chr18-36371033-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.273-1647C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 152,046 control chromosomes in the GnomAD database, including 14,859 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 0.43 (14859 hom., cov: 32)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.568

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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.273-1647C>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.273-1647C>T		intron_variant		1	NM_001281740.3	ENSP00000466937	A2
FHOD3	ENST00000257209.8	c.273-1647C>T		intron_variant		1		ENSP00000257209	P4
FHOD3	ENST00000359247.8	c.273-1647C>T		intron_variant		1		ENSP00000352186	A2
FHOD3	ENST00000589114.5	n.392-1647C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64894 AN: 151928 Hom.: 14825 Cov.: 32

Gnomad AFR AF: 0.558

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.435

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

GnomAD4 genome AF: 0.427 AC: 64985 AN: 152046 Hom.: 14859 Cov.: 32 AF XY: 0.430 AC XY: 31931 AN XY: 74308

Gnomad4 AFR AF: 0.559

Gnomad4 AMR AF: 0.348

Gnomad4 ASJ AF: 0.448

Gnomad4 EAS AF: 0.664

Gnomad4 SAS AF: 0.639

Gnomad4 FIN AF: 0.355

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.440

Alfa AF: 0.368 Hom.: 1869

Bravo AF: 0.426

Asia WGS AF: 0.650 AC: 2259 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.25
DANN	Benign	0.53

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: rs1893271; hg19: chr18-33950996;