18-36355736-A-C

Variant names:

• chr18-36355736-A-C
• rs79498577
• NM_001281740.3:c.272+91A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001281740.3(FHOD3):​c.272+91A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000113 in 887,010 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.272+91A>C		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.272+91A>C		intron_variant	Intron 2 of 28	1	NM_001281740.3	ENSP00000466937.1
FHOD3	ENST00000257209.8	c.272+91A>C		intron_variant	Intron 2 of 24	1		ENSP00000257209.3
FHOD3	ENST00000359247.8	c.272+91A>C		intron_variant	Intron 2 of 23	1		ENSP00000352186.3
FHOD3	ENST00000589114.5	n.391+91A>C		intron_variant	Intron 2 of 13	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000113 AC: 1 AN: 887010 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 455690

African (AFR) AF: 0.00 AC: 0 AN: 21850

American (AMR) AF: 0.00 AC: 0 AN: 33144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19756

East Asian (EAS) AF: 0.00 AC: 0 AN: 34362

South Asian (SAS) AF: 0.00 AC: 0 AN: 65136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3420

European-Non Finnish (NFE) AF: 0.00000161 AC: 1 AN: 622530

Other (OTH) AF: 0.00 AC: 0 AN: 41058

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 86

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.81
DANN	Benign	0.75
PhyloP100		-1.7

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: rs79498577; hg19: chr18-33935699;