rs755501978

Variant names:

• chr18-36297915-G-A
• NM_001281740.3:c.80G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-36297915-G-A
• chr18-36297915-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001281740.3(FHOD3):​c.80G>A​(p.Arg27Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000071 in 1,407,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FHOD3 NM_001281740.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.92

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3222347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.80G>A	p.Arg27Gln	missense_variant	Exon 1 of 29	ENST00000590592.6	NP_001268669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHOD3	ENST00000590592.6	c.80G>A	p.Arg27Gln	missense_variant	Exon 1 of 29	1	NM_001281740.3	ENSP00000466937.1
FHOD3	ENST00000257209.8	c.80G>A	p.Arg27Gln	missense_variant	Exon 1 of 25	1		ENSP00000257209.3
FHOD3	ENST00000359247.8	c.80G>A	p.Arg27Gln	missense_variant	Exon 1 of 24	1		ENSP00000352186.3
FHOD3	ENST00000589114.5	n.199G>A		non_coding_transcript_exon_variant	Exon 1 of 14	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1407664 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 696008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	.;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.63	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.6	M;M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.6	D;.;D
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D;.;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.27
MutPred		0.39		Loss of glycosylation at S26 (P = 0.0833);Loss of glycosylation at S26 (P = 0.0833);Loss of glycosylation at S26 (P = 0.0833);
MVP		0.19
MPC		2.5
ClinPred		0.98	D
GERP RS		3.2
Varity_R		0.44
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-33877878;