Variant chr18-36501886-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.33

Variant links:

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]

FHOD3 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.338-46A>G		intron_variant		ENST00000590592.6

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
FHOD3	ENST00000590592.6 linkuse as main transcript	c.338-46A>G	intron_variant	1	NM_001281740.3	A2	Q2V2M9-4
FHOD3	ENST00000257209.8 linkuse as main transcript	c.338-46A>G	intron_variant	1		P4	Q2V2M9-3
FHOD3	ENST00000359247.8 linkuse as main transcript	c.338-46A>G	intron_variant	1		A2	Q2V2M9-1
FHOD3	ENST00000589114.5 linkuse as main transcript	n.457-46A>G	intron_variant, non_coding_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.341

AC:

51836

AN:

151998

Hom.:

9748

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.387

AC XY:

227380

AN XY:

587198

show subpopulations

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.:

AF XY:

0.337

AC XY:

25040

AN XY:

74372

show subpopulations

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

LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over