dbSNP rs3744903: FHOD3:p.Asn1159Asn (chr18-36730705-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001281740.3(FHOD3):c.3477C>T(p.Asn1159Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,613,170 control chromosomes in the GnomAD database, including 94,866 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7308 hom., cov: 32)

Exomes 𝑓: 0.34 ( 87558 hom. )

Consequence

FHOD3
NM_001281740.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.500

Publications

26 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, ClinGen
cardiomyopathy, familial hypertrophic, 28
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

FHOD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 18-36730705-C-T is Benign according to our data. Variant chr18-36730705-C-T is described in ClinVar as Benign. ClinVar VariationId is 1239394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.5 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001281740.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FHOD3	NM_001281740.3	MANE Select	c.3477C>T	p.Asn1159Asn	synonymous	Exon 20 of 29	NP_001268669.1	Q2V2M9-4
FHOD3	NM_025135.5		c.2952C>T	p.Asn984Asn	synonymous	Exon 17 of 25	NP_079411.2
FHOD3	NM_001281739.3		c.2901C>T	p.Asn967Asn	synonymous	Exon 16 of 24	NP_001268668.1	Q2V2M9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FHOD3	ENST00000590592.6	TSL:1 MANE Select	c.3477C>T	p.Asn1159Asn	synonymous	Exon 20 of 29	ENSP00000466937.1	Q2V2M9-4
FHOD3	ENST00000257209.8	TSL:1	c.2952C>T	p.Asn984Asn	synonymous	Exon 17 of 25	ENSP00000257209.3	Q2V2M9-3
FHOD3	ENST00000359247.8	TSL:1	c.2901C>T	p.Asn967Asn	synonymous	Exon 16 of 24	ENSP00000352186.3	Q2V2M9-1

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45490

AN:

151946

Hom.:

7298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.346

Gnomad AMR

AF:

0.406

Gnomad ASJ

AF:

0.298

Gnomad EAS

AF:

0.309

Gnomad SAS

AF:

0.446

Gnomad FIN

AF:

0.275

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.337

Gnomad OTH

AF:

0.328

GnomAD2 exomes

AF:

0.350

AC:

87893

AN:

251090

AF XY:

0.353

show subpopulations

Gnomad AFR exome

AF:

0.183

Gnomad AMR exome

AF:

0.491

Gnomad ASJ exome

AF:

0.307

Gnomad EAS exome

AF:

0.295

Gnomad FIN exome

AF:

0.279

Gnomad NFE exome

AF:

0.330

Gnomad OTH exome

AF:

0.353

GnomAD4 exome

AF:

0.342

AC:

499219

AN:

1461106

Hom.:

87558

Cov.:

AF XY:

0.345

AC XY:

250445

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.177

AC:

5915

AN:

33472

American (AMR)

AF:

0.484

AC:

21596

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

7945

AN:

26116

East Asian (EAS)

AF:

0.299

AC:

11874

AN:

39682

South Asian (SAS)

AF:

0.448

AC:

38640

AN:

86174

European-Finnish (FIN)

AF:

0.276

AC:

14768

AN:

53416

Middle Eastern (MID)

AF:

0.368

AC:

2118

AN:

5762

European-Non Finnish (NFE)

AF:

0.338

AC:

375964

AN:

1111488

Other (OTH)

AF:

0.338

AC:

20399

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

16649

33298

49948

66597

83246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12224

24448

36672

48896

61120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.299

AC:

45510

AN:

152064

Hom.:

7308

Cov.:

AF XY:

0.302

AC XY:

22426

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.183

AC:

7575

AN:

41502

American (AMR)

AF:

0.406

AC:

6215

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.298

AC:

1033

AN:

3472

East Asian (EAS)

AF:

0.309

AC:

1596

AN:

5160

South Asian (SAS)

AF:

0.446

AC:

2148

AN:

4820

European-Finnish (FIN)

AF:

0.275

AC:

2897

AN:

10542

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.337

AC:

22935

AN:

67962

Other (OTH)

AF:

0.328

AC:

693

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1601

3201

4802

6402

8003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

478

956

1434

1912

2390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.328

Hom.:

13944

Bravo

AF:

0.299

Asia WGS

AF:

0.379

AC:

1318

AN:

3478

EpiCase

AF:

0.344

EpiControl

AF:

0.345

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

2.5

(source)

DANN

Benign

0.68

PhyloP100

-0.50

PromoterAI

-0.066

Neutral

(source)

Mutation Taster

=293/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over