rs188660514

Variant names:

• chr18-36297724-T-A
• rs188660514
• NM_001281740.3:c.-112T>A

Your query was ambiguous. Multiple possible variants found:

• chr18-36297724-T-A
• chr18-36297724-T-C
• chr18-36297724-T-G

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.-112T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 28)
  • Exomes 𝑓: 0.0000033 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FHOD3 NM_001281740.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.595
• 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: 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=-0.68).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.-112T>A		5_prime_UTR_variant	Exon 1 of 29	ENST00000590592.6	NP_001268669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHOD3	ENST00000590592.6	c.-112T>A		5_prime_UTR_variant	Exon 1 of 29	1	NM_001281740.3	ENSP00000466937.1
FHOD3	ENST00000257209.8	c.-112T>A		5_prime_UTR_variant	Exon 1 of 25	1		ENSP00000257209.3
FHOD3	ENST00000589114.5	n.8T>A		non_coding_transcript_exon_variant	Exon 1 of 14	2
FHOD3	ENST00000359247.8	c.-112T>A		upstream_gene_variant		1		ENSP00000352186.3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000328 AC: 2 AN: 609842 Hom.: 0 Cov.: 8 AF XY: 0.00000684 AC XY: 2 AN XY: 292510

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000864 AC: 1 AN: 11570

American (AMR) AF: 0.00 AC: 0 AN: 3368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6428

East Asian (EAS) AF: 0.00 AC: 0 AN: 11164

South Asian (SAS) AF: 0.00 AC: 0 AN: 11548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1616

European-Non Finnish (NFE) AF: 0.00000193 AC: 1 AN: 517084

Other (OTH) AF: 0.00 AC: 0 AN: 22494

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.90
PhyloP100		0.59
PromoterAI		0.012	Neutral

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: rs188660514; hg19: chr18-33877687;