chr18-36297915-G-C

Position:

chr18-36297915-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001281740.3(FHOD3):c.80G>C(p.Arg27Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000391 in 1,559,724 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

FHOD3
NM_001281740.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.92

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26117665).

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHOD3	NM_001281740.3 linkuse as main transcript	c.80G>C	p.Arg27Pro	missense_variant	1/29	ENST00000590592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHOD3	ENST00000590592.6 linkuse as main transcript	c.80G>C	p.Arg27Pro	missense_variant	1/29	1	NM_001281740.3	A2	Q2V2M9-4
FHOD3	ENST00000257209.8 linkuse as main transcript	c.80G>C	p.Arg27Pro	missense_variant	1/25	1		P4	Q2V2M9-3
FHOD3	ENST00000359247.8 linkuse as main transcript	c.80G>C	p.Arg27Pro	missense_variant	1/24	1		A2	Q2V2M9-1
FHOD3	ENST00000589114.5 linkuse as main transcript	n.199G>C		non_coding_transcript_exon_variant	1/14	2

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000156

AC:

AN:

166500

Hom.:

AF XY:

0.000134

AC XY:

AN XY:

89828

show subpopulations

Gnomad AFR exome

AF:

0.000253

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000333

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.000411

AC:

579

AN:

1407664

Hom.:

Cov.:

AF XY:

0.000385

AC XY:

268

AN XY:

696008

show subpopulations

Gnomad4 AFR exome

AF:

0.0000648

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000798

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000516

Gnomad4 OTH exome

AF:

0.000257

GnomAD4 genome

AF:

0.000204

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.000181

ExAC

AF:

0.0000945

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.80G>C (p.R27P) alteration is located in exon 1 (coding exon 1) of the FHOD3 gene. This alteration results from a G to C substitution at nucleotide position 80, causing the arginine (R) at amino acid position 27 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiomyopathy, familial hypertrophic, 28

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, dominant-negative has been suggested for a single missense variant (PMID: 24088304). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to proline. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 32 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

.;.;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.6

M;M;M

MutationTaster

Benign

0.97

D;D;D;D

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-4.6

D;.;D

REVEL

Benign

0.14

Sift

Uncertain

0.0020

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.099

B;.;D

Vest4

0.33

MVP

0.17

MPC

3.1

ClinPred

0.80

GERP RS

3.2

Varity_R

0.85

gMVP

0.74

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