18-36297750-G-T

Variant names:

• chr18-36297750-G-T
• rs141472663
• NM_001281740.3:c.-86G>T

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.195
• Publications: 4 publications found

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):

• cardiomyopathy, familial hypertrophic, 28

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.-86G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 29	ENST00000590592.6	NP_001268669.1
FHOD3	NM_001281740.3	c.-86G>T		5_prime_UTR_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.-86G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 29	1	NM_001281740.3	ENSP00000466937.1
FHOD3	ENST00000590592.6	c.-86G>T		5_prime_UTR_variant	Exon 1 of 29	1	NM_001281740.3	ENSP00000466937.1

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

African (AFR) AF: 0.106 AC: 2027 AN: 19180

American (AMR) AF: 0.190 AC: 1371 AN: 7220

Ashkenazi Jewish (ASJ) AF: 0.0952 AC: 1167 AN: 12260

East Asian (EAS) AF: 0.170 AC: 3833 AN: 22510

South Asian (SAS) AF: 0.0832 AC: 2352 AN: 28254

European-Finnish (FIN) AF: 0.0677 AC: 2399 AN: 35426

Middle Eastern (MID) AF: 0.107 AC: 333 AN: 3114

European-Non Finnish (NFE) AF: 0.0793 AC: 64383 AN: 811912

Other (OTH) AF: 0.0991 AC: 3787 AN: 38204

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

African (AFR) AF: 0.101 AC: 4164 AN: 41126

American (AMR) AF: 0.159 AC: 2391 AN: 15050

Ashkenazi Jewish (ASJ) AF: 0.0917 AC: 315 AN: 3434

East Asian (EAS) AF: 0.157 AC: 794 AN: 5058

South Asian (SAS) AF: 0.0714 AC: 344 AN: 4816

European-Finnish (FIN) AF: 0.0676 AC: 654 AN: 9670

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 290

European-Non Finnish (NFE) AF: 0.0823 AC: 5534 AN: 67206

Other (OTH) AF: 0.0988 AC: 206 AN: 2086

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 23, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		0.20
PromoterAI		-0.28	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs141472663; hg19: chr18-33877713;