18-36640528-T-C

Variant names:

• chr18-36640528-T-C
• rs2644261
• NM_001281740.3:c.1197-8788T>C

Variant summary

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

The NM_001281740.3(FHOD3):​c.1197-8788T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 152,102 control chromosomes in the GnomAD database, including 12,693 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 0.39 (12693 hom., cov: 32)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.1197-8788T>C		intron_variant	Intron 10 of 28	ENST00000590592.6	NP_001268669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHOD3	ENST00000590592.6	c.1197-8788T>C		intron_variant	Intron 10 of 28	1	NM_001281740.3	ENSP00000466937.1

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59655 AN: 151984 Hom.: 12674 Cov.: 32

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.386

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

GnomAD4 genome AF: 0.393 AC: 59719 AN: 152102 Hom.: 12693 Cov.: 32 AF XY: 0.390 AC XY: 28996 AN XY: 74374

Gnomad4 AFR AF: 0.545

Gnomad4 AMR AF: 0.442

Gnomad4 ASJ AF: 0.350

Gnomad4 EAS AF: 0.434

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.387

Alfa AF: 0.352 Hom.: 4985

Bravo AF: 0.414

Asia WGS AF: 0.468 AC: 1625 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.61

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: rs2644261; hg19: chr18-34220491;