rs2303508

Positions:

• chr18-36744413-A-G
• chr18-36744413-A-T

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.4041+220A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.507 in 152,186 control chromosomes in the GnomAD database, including 20,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.51 (20000 hom., cov: 34)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.36

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=-0.7).
• BP6: Variant 18-36744413-A-G is Benign according to our data. Variant chr18-36744413-A-G is described in ClinVar as [Benign]. Clinvar id is 1236859.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHOD3	NM_001281740.3	c.4041+220A>G		intron_variant		ENST00000590592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHOD3	ENST00000590592.6	c.4041+220A>G		intron_variant		1	NM_001281740.3	A2

Frequencies

GnomAD3 genomes AF: 0.507 AC: 77114 AN: 152068 Hom.: 19959 Cov.: 34

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.499

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

GnomAD4 genome AF: 0.507 AC: 77211 AN: 152186 Hom.: 20000 Cov.: 34 AF XY: 0.506 AC XY: 37659 AN XY: 74388

Gnomad4 AFR AF: 0.610

Gnomad4 AMR AF: 0.526

Gnomad4 ASJ AF: 0.409

Gnomad4 EAS AF: 0.313

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.438

Gnomad4 NFE AF: 0.470

Gnomad4 OTH AF: 0.498

Alfa AF: 0.480 Hom.: 9085

Bravo AF: 0.515

Asia WGS AF: 0.437 AC: 1520 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

Sep 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.70

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: rs2303508; hg19: chr18-34324376;