18-36502297-G-A

Position:

• chr18-36502297-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001281740.3(FHOD3):​c.405+298G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0921 in 149,906 control chromosomes in the GnomAD database, including 898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.092 (898 hom., cov: 31)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.24

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 18-36502297-G-A is Benign according to our data. Variant chr18-36502297-G-A is described in ClinVar as [Benign]. Clinvar id is 1223337.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHOD3	NM_001281740.3	c.405+298G>A		intron_variant		ENST00000590592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHOD3	ENST00000590592.6	c.405+298G>A		intron_variant		1	NM_001281740.3	A2
FHOD3	ENST00000257209.8	c.405+298G>A		intron_variant		1		P4
FHOD3	ENST00000359247.8	c.405+298G>A		intron_variant		1		A2
FHOD3	ENST00000589114.5	n.524+298G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0923 AC: 13820 AN: 149796 Hom.: 898 Cov.: 31

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.0584

Gnomad AMR AF: 0.0666

Gnomad ASJ AF: 0.0814

Gnomad EAS AF: 0.00237

Gnomad SAS AF: 0.0454

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.0545

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.0882

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

GnomAD4 genome AF: 0.0921 AC: 13812 AN: 149906 Hom.: 898 Cov.: 31 AF XY: 0.0919 AC XY: 6711 AN XY: 73028

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.0664

Gnomad4 ASJ AF: 0.0814

Gnomad4 EAS AF: 0.00238

Gnomad4 SAS AF: 0.0449

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.0867

Alfa AF: 0.101 Hom.: 101

Bravo AF: 0.0807

Asia WGS AF: 0.0270 AC: 92 AN: 3478

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

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.21
DANN	Benign	0.13

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: rs140979832; hg19: chr18-34082260;