18-36371033-C-T

Variant names:

• chr18-36371033-C-T
• rs1893271
• NM_001281740.3:c.273-1647C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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):

• cardiomyopathy, familial hypertrophic, 28

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

  Inheritance: AD Classification: MODERATE Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.273-1647C>T		intron_variant	Intron 2 of 28	ENST00000590592.6	NP_001268669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHOD3	ENST00000590592.6	c.273-1647C>T		intron_variant	Intron 2 of 28	1	NM_001281740.3	ENSP00000466937.1
FHOD3	ENST00000257209.8	c.273-1647C>T		intron_variant	Intron 2 of 24	1		ENSP00000257209.3
FHOD3	ENST00000359247.8	c.273-1647C>T		intron_variant	Intron 2 of 23	1		ENSP00000352186.3
FHOD3	ENST00000589114.5	n.392-1647C>T		intron_variant	Intron 2 of 13	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

African (AFR) AF: 0.559 AC: 23141 AN: 41432

American (AMR) AF: 0.348 AC: 5321 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1553 AN: 3470

East Asian (EAS) AF: 0.664 AC: 3431 AN: 5170

South Asian (SAS) AF: 0.639 AC: 3080 AN: 4820

European-Finnish (FIN) AF: 0.355 AC: 3759 AN: 10578

Middle Eastern (MID) AF: 0.517 AC: 150 AN: 290

European-Non Finnish (NFE) AF: 0.342 AC: 23280 AN: 67978

Other (OTH) AF: 0.440 AC: 929 AN: 2112

Alfa AF: 0.378 Hom.: 17145

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
PhyloP100		-0.57
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: rs1893271; hg19: chr18-33950996;