18-36501886-A-G

Position:

• chr18-36501886-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.338-46A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,319,520 control chromosomes in the GnomAD database, including 103,773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9746 hom., cov: 32)
  • Exomes 𝑓: 0.39 (94027 hom.)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.33

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=-0.86).
• BP6: Variant 18-36501886-A-G is Benign according to our data. Variant chr18-36501886-A-G is described in ClinVar as [Benign]. Clinvar id is 1290953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHOD3	NM_001281740.3	c.338-46A>G		intron_variant		ENST00000590592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHOD3	ENST00000590592.6	c.338-46A>G		intron_variant		1	NM_001281740.3	A2
FHOD3	ENST00000257209.8	c.338-46A>G		intron_variant		1		P4
FHOD3	ENST00000359247.8	c.338-46A>G		intron_variant		1		A2
FHOD3	ENST00000589114.5	n.457-46A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51836 AN: 151998 Hom.: 9748 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.341

GnomAD3 exomes AF: 0.320 AC: 51827 AN: 162028 Hom.: 9770 AF XY: 0.323 AC XY: 27909 AN XY: 86376

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.0406

Gnomad SAS exome AF: 0.254

Gnomad FIN exome AF: 0.418

Gnomad NFE exome AF: 0.424

Gnomad OTH exome AF: 0.357

GnomAD4 exome AF: 0.390 AC: 455567 AN: 1167404 Hom.: 94027 Cov.: 15 AF XY: 0.387 AC XY: 227380 AN XY: 587198

Gnomad4 AFR exome AF: 0.245

Gnomad4 AMR exome AF: 0.209

Gnomad4 ASJ exome AF: 0.281

Gnomad4 EAS exome AF: 0.0532

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.413

Gnomad4 NFE exome AF: 0.429

Gnomad4 OTH exome AF: 0.364

GnomAD4 genome AF: 0.341 AC: 51843 AN: 152116 Hom.: 9746 Cov.: 32 AF XY: 0.337 AC XY: 25040 AN XY: 74372

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.0495

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.424

Gnomad4 NFE AF: 0.431

Gnomad4 OTH AF: 0.337

Alfa AF: 0.394 Hom.: 17432

Bravo AF: 0.325

Asia WGS AF: 0.167 AC: 582 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.86
CADD	Benign	0.076
DANN	Benign	0.40

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: rs17565834; hg19: chr18-34081849;