NM_001281740.3:c.405+254_405+255delTT

Variant names:

• chr18-36502240-GTT-G
• rs5824024
• NM_001281740.3:c.405+254_405+255delTT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001281740.3(FHOD3):​c.405+254_405+255delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0031 (0 hom., cov: 0)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0900

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 447 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.405+254_405+255delTT		intron_variant	Intron 4 of 28	ENST00000590592.6	NP_001268669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHOD3	ENST00000590592.6	c.405+242_405+243delTT		intron_variant	Intron 4 of 28	1	NM_001281740.3	ENSP00000466937.1
FHOD3	ENST00000257209.8	c.405+242_405+243delTT		intron_variant	Intron 4 of 24	1		ENSP00000257209.3
FHOD3	ENST00000359247.8	c.405+242_405+243delTT		intron_variant	Intron 4 of 23	1		ENSP00000352186.3
FHOD3	ENST00000589114.5	n.524+242_524+243delTT		intron_variant	Intron 4 of 13	2

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 447 AN: 146170 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00845

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00109

Gnomad FIN AF: 0.000542

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00380

Gnomad OTH AF: 0.00801

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

GnomAD4 genome AF: 0.00306 AC: 447 AN: 146232 Hom.: 0 Cov.: 0 AF XY: 0.00301 AC XY: 214 AN XY: 71086

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00845

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00109

Gnomad4 FIN AF: 0.000542

Gnomad4 NFE AF: 0.00380

Gnomad4 OTH AF: 0.00796

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs5824024; hg19: chr18-34082203;