chr18-36502240-GT-G

Position:

• chr18-36502240-GT-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001281740.3(FHOD3):​c.405+255del variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.35 (8896 hom., cov: 0)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.554

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 18-36502240-GT-G is Benign according to our data. Variant chr18-36502240-GT-G is described in ClinVar as [Benign]. Clinvar id is 1246300.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHOD3	NM_001281740.3	c.405+255del		intron_variant		ENST00000590592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHOD3	ENST00000590592.6	c.405+255del		intron_variant		1	NM_001281740.3	A2
FHOD3	ENST00000257209.8	c.405+255del		intron_variant		1		P4
FHOD3	ENST00000359247.8	c.405+255del		intron_variant		1		A2
FHOD3	ENST00000589114.5	n.524+255del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.346 AC: 50480 AN: 146026 Hom.: 8897 Cov.: 0

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.0692

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.375

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.336

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

GnomAD4 genome AF: 0.346 AC: 50499 AN: 146086 Hom.: 8896 Cov.: 0 AF XY: 0.341 AC XY: 24195 AN XY: 70992

Gnomad4 AFR AF: 0.310

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.285

Gnomad4 EAS AF: 0.0692

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.400

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.333

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 2021

- -

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;