18-36297724-T-C

Position:

• chr18-36297724-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001281740.3(FHOD3):​c.-112T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.895 in 756,258 control chromosomes in the GnomAD database, including 303,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (60152 hom., cov: 28)
  • Exomes 𝑓: 0.89 (243100 hom.)
• Consequence: FHOD3 NM_001281740.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.595

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 18-36297724-T-C is Benign according to our data. Variant chr18-36297724-T-C is described in ClinVar as [Benign]. Clinvar id is 1221085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHOD3	NM_001281740.3	c.-112T>C		5_prime_UTR_variant	1/29	ENST00000590592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHOD3	ENST00000590592.6	c.-112T>C		5_prime_UTR_variant	1/29	1	NM_001281740.3	A2
FHOD3	ENST00000257209.8	c.-112T>C		5_prime_UTR_variant	1/25	1		P4
FHOD3	ENST00000589114.5	n.8T>C		non_coding_transcript_exon_variant	1/14	2

Frequencies

GnomAD3 genomes AF: 0.902 AC: 132979 AN: 147390 Hom.: 60098 Cov.: 28

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.942

Gnomad AMR AF: 0.906

Gnomad ASJ AF: 0.771

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.910

Gnomad MID AF: 0.795

Gnomad NFE AF: 0.892

Gnomad OTH AF: 0.879

GnomAD4 exome AF: 0.893 AC: 543542 AN: 608764 Hom.: 243100 Cov.: 8 AF XY: 0.892 AC XY: 260369 AN XY: 291964

Gnomad4 AFR exome AF: 0.929

Gnomad4 AMR exome AF: 0.901

Gnomad4 ASJ exome AF: 0.773

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.776

Gnomad4 FIN exome AF: 0.895

Gnomad4 NFE exome AF: 0.895

Gnomad4 OTH exome AF: 0.879

GnomAD4 genome AF: 0.902 AC: 133085 AN: 147494 Hom.: 60152 Cov.: 28 AF XY: 0.902 AC XY: 64882 AN XY: 71912

Gnomad4 AFR AF: 0.928

Gnomad4 AMR AF: 0.906

Gnomad4 ASJ AF: 0.771

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.804

Gnomad4 FIN AF: 0.910

Gnomad4 NFE AF: 0.892

Gnomad4 OTH AF: 0.879

Alfa AF: 0.884 Hom.: 2700

Bravo AF: 0.906

Asia WGS AF: 0.909 AC: 2895 AN: 3188

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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	-0.79
CADD	Benign	18
DANN	Benign	0.80

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

Other links and lift over

dbSNP: rs188660514; hg19: chr18-33877687;