NM_001281740.3:c.511+27649C>T

Variant names:

• chr18-36540192-C-T
• rs10502661
• NM_001281740.3:c.511+27649C>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.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
• Publications: 4 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=-0.54).
• 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 rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.511+27649C>T		intron_variant	Intron 5 of 28	ENST00000590592.6	NP_001268669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHOD3	ENST00000590592.6	c.511+27649C>T		intron_variant	Intron 5 of 28	1	NM_001281740.3	ENSP00000466937.1
FHOD3	ENST00000257209.8	c.511+27649C>T		intron_variant	Intron 5 of 24	1		ENSP00000257209.3
FHOD3	ENST00000359247.8	c.511+27649C>T		intron_variant	Intron 5 of 23	1		ENSP00000352186.3
FHOD3	ENST00000589114.5	n.630+27649C>T		intron_variant	Intron 5 of 13	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

African (AFR) AF: 0.0289 AC: 1202 AN: 41534

American (AMR) AF: 0.139 AC: 2127 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3472

East Asian (EAS) AF: 0.0511 AC: 265 AN: 5182

South Asian (SAS) AF: 0.222 AC: 1068 AN: 4820

European-Finnish (FIN) AF: 0.0425 AC: 451 AN: 10604

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0682 AC: 4635 AN: 68006

Other (OTH) AF: 0.0559 AC: 118 AN: 2110

Alfa AF: 0.0766 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
PhyloP100		0.36
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: rs10502661; hg19: chr18-34120155;