NM_001281740.3:c.272+91A>G

Variant names:

• chr18-36355736-A-G
• rs79498577
• NM_001281740.3:c.272+91A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• cardiomyopathy, familial hypertrophic, 28

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.272+91A>G		intron_variant	Intron 2 of 28	ENST00000590592.6	NP_001268669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHOD3	ENST00000590592.6	c.272+91A>G		intron_variant	Intron 2 of 28	1	NM_001281740.3	ENSP00000466937.1
FHOD3	ENST00000257209.8	c.272+91A>G		intron_variant	Intron 2 of 24	1		ENSP00000257209.3
FHOD3	ENST00000359247.8	c.272+91A>G		intron_variant	Intron 2 of 23	1		ENSP00000352186.3
FHOD3	ENST00000589114.5	n.391+91A>G		intron_variant	Intron 2 of 13	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

African (AFR) AF: 0.00174 AC: 38 AN: 21850

American (AMR) AF: 0.00935 AC: 310 AN: 33144

Ashkenazi Jewish (ASJ) AF: 0.00537 AC: 106 AN: 19756

East Asian (EAS) AF: 0.248 AC: 8515 AN: 34318

South Asian (SAS) AF: 0.0147 AC: 959 AN: 65130

European-Finnish (FIN) AF: 0.00634 AC: 290 AN: 45754

Middle Eastern (MID) AF: 0.00409 AC: 14 AN: 3420

European-Non Finnish (NFE) AF: 0.00303 AC: 1887 AN: 622514

Other (OTH) AF: 0.0212 AC: 871 AN: 41050

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

African (AFR) AF: 0.00221 AC: 92 AN: 41570

American (AMR) AF: 0.00876 AC: 134 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.272 AC: 1399 AN: 5152

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4826

European-Finnish (FIN) AF: 0.00763 AC: 81 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00415 AC: 282 AN: 68018

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.0202 Hom.: 86

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 23, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.99
DANN	Benign	0.69
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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