18-36355736-A-G

Position:

• chr18-36355736-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001281740.3(FHOD3):​c.272+91A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,039,204 control chromosomes in the GnomAD database, including 1,406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (200 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1206 hom.)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.70

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 18-36355736-A-G is Benign according to our data. Variant chr18-36355736-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1317403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHOD3	NM_001281740.3	c.272+91A>G		intron_variant		ENST00000590592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHOD3	ENST00000590592.6	c.272+91A>G		intron_variant		1	NM_001281740.3	A2
FHOD3	ENST00000257209.8	c.272+91A>G		intron_variant		1		P4
FHOD3	ENST00000359247.8	c.272+91A>G		intron_variant		1		A2
FHOD3	ENST00000589114.5	n.391+91A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2151 AN: 152150 Hom.: 200 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00871

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00415

Gnomad OTH AF: 0.0162

GnomAD4 exome AF: 0.0146 AC: 12990 AN: 886936 Hom.: 1206 AF XY: 0.0147 AC XY: 6713 AN XY: 455648

Gnomad4 AFR exome AF: 0.00174

Gnomad4 AMR exome AF: 0.00935

Gnomad4 ASJ exome AF: 0.00537

Gnomad4 EAS exome AF: 0.248

Gnomad4 SAS exome AF: 0.0147

Gnomad4 FIN exome AF: 0.00634

Gnomad4 NFE exome AF: 0.00303

Gnomad4 OTH exome AF: 0.0212

GnomAD4 genome AF: 0.0141 AC: 2153 AN: 152268 Hom.: 200 Cov.: 32 AF XY: 0.0152 AC XY: 1129 AN XY: 74448

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00876

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.00763

Gnomad4 NFE AF: 0.00415

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00374 Hom.: 1

Bravo AF: 0.0157

Asia WGS AF: 0.120 AC: 416 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.99
DANN	Benign	0.69

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: rs79498577; hg19: chr18-33935699; COSMIC: COSV57167396;