rs12971184

Variant names:

• chr18-36300722-G-A
• rs12971184
• NM_001281740.3:c.165+2722G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001281740.3(FHOD3):​c.165+2722G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 150,978 control chromosomes in the GnomAD database, including 1,815 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 0.14 (1815 hom., cov: 31)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.992
• Publications: 1 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.165+2722G>A		intron_variant	Intron 1 of 28	ENST00000590592.6	NP_001268669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHOD3	ENST00000590592.6	c.165+2722G>A		intron_variant	Intron 1 of 28	1	NM_001281740.3	ENSP00000466937.1
FHOD3	ENST00000257209.8	c.165+2722G>A		intron_variant	Intron 1 of 24	1		ENSP00000257209.3
FHOD3	ENST00000359247.8	c.165+2722G>A		intron_variant	Intron 1 of 23	1		ENSP00000352186.3
FHOD3	ENST00000589114.5	n.284+2722G>A		intron_variant	Intron 1 of 13	2

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20736 AN: 150858 Hom.: 1818 Cov.: 31

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.161

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

GnomAD4 genome AF: 0.137 AC: 20723 AN: 150978 Hom.: 1815 Cov.: 31 AF XY: 0.140 AC XY: 10354 AN XY: 73718

African (AFR) AF: 0.0362 AC: 1491 AN: 41164

American (AMR) AF: 0.137 AC: 2054 AN: 15006

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 583 AN: 3460

East Asian (EAS) AF: 0.250 AC: 1265 AN: 5054

South Asian (SAS) AF: 0.249 AC: 1187 AN: 4772

European-Finnish (FIN) AF: 0.170 AC: 1793 AN: 10522

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11825 AN: 67708

Other (OTH) AF: 0.158 AC: 331 AN: 2094

Alfa AF: 0.134 Hom.: 203

Bravo AF: 0.128

Asia WGS AF: 0.217 AC: 757 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.6
DANN	Benign	0.42
PhyloP100		0.99
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: rs12971184; hg19: chr18-33880685;