chr18-36297750-G-T

Position:

• chr18-36297750-G-T

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.-86G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0853 in 1,127,724 control chromosomes in the GnomAD database, including 4,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (752 hom., cov: 32)
  • Exomes 𝑓: 0.083 (3685 hom.)
• Consequence: FHOD3 NM_001281740.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.195

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=-0.56).
• BP6: Variant 18-36297750-G-T is Benign according to our data. Variant chr18-36297750-G-T is described in ClinVar as [Benign]. Clinvar id is 1287000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHOD3	NM_001281740.3	c.-86G>T		5_prime_UTR_variant	1/29	ENST00000590592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHOD3	ENST00000590592.6	c.-86G>T		5_prime_UTR_variant	1/29	1	NM_001281740.3	A2
FHOD3	ENST00000257209.8	c.-86G>T		5_prime_UTR_variant	1/25	1		P4
FHOD3	ENST00000589114.5	n.34G>T		non_coding_transcript_exon_variant	1/14	2

Frequencies

GnomAD3 genomes AF: 0.0972 AC: 14530 AN: 149538 Hom.: 752 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.0917

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.0718

Gnomad FIN AF: 0.0676

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.0823

Gnomad OTH AF: 0.0979

GnomAD4 exome AF: 0.0835 AC: 81652 AN: 978080 Hom.: 3685 Cov.: 13 AF XY: 0.0838 AC XY: 39653 AN XY: 473074

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.190

Gnomad4 ASJ exome AF: 0.0952

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.0832

Gnomad4 FIN exome AF: 0.0677

Gnomad4 NFE exome AF: 0.0793

Gnomad4 OTH exome AF: 0.0991

GnomAD4 genome AF: 0.0971 AC: 14533 AN: 149644 Hom.: 752 Cov.: 32 AF XY: 0.0986 AC XY: 7207 AN XY: 73084

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.0917

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.0714

Gnomad4 FIN AF: 0.0676

Gnomad4 NFE AF: 0.0823

Gnomad4 OTH AF: 0.0988

Alfa AF: 0.0918 Hom.: 81

Bravo AF: 0.105

Asia WGS AF: 0.123 AC: 417 AN: 3406

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	Feb 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.90

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: rs141472663; hg19: chr18-33877713;