chr18-36297724-T-C

Variant names:

• chr18-36297724-T-C
• rs188660514
• NM_001281740.3:c.-112T>C

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.-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
• 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=-0.79).
• 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 rank	MANE	Protein	UniProt
FHOD3	NM_001281740.3	c.-112T>C		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.-112T>C		5_prime_UTR_variant	Exon 1 of 29	1	NM_001281740.3	ENSP00000466937.1
FHOD3	ENST00000257209.8	c.-112T>C		5_prime_UTR_variant	Exon 1 of 25	1		ENSP00000257209.3
FHOD3	ENST00000589114.5	n.8T>C		non_coding_transcript_exon_variant	Exon 1 of 14	2
FHOD3	ENST00000359247.8	c.-112T>C		upstream_gene_variant		1		ENSP00000352186.3

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

African (AFR) AF: 0.929 AC: 10732 AN: 11558

American (AMR) AF: 0.901 AC: 3027 AN: 3360

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 4946 AN: 6398

East Asian (EAS) AF: 0.999 AC: 11152 AN: 11164

South Asian (SAS) AF: 0.776 AC: 8925 AN: 11498

European-Finnish (FIN) AF: 0.895 AC: 21959 AN: 24532

Middle Eastern (MID) AF: 0.773 AC: 1246 AN: 1612

European-Non Finnish (NFE) AF: 0.895 AC: 461828 AN: 516194

Other (OTH) AF: 0.879 AC: 19727 AN: 22448

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

African (AFR) AF: 0.928 AC: 37909 AN: 40832

American (AMR) AF: 0.906 AC: 13528 AN: 14926

Ashkenazi Jewish (ASJ) AF: 0.771 AC: 2629 AN: 3410

East Asian (EAS) AF: 0.997 AC: 4949 AN: 4966

South Asian (SAS) AF: 0.804 AC: 3843 AN: 4782

European-Finnish (FIN) AF: 0.910 AC: 8234 AN: 9046

Middle Eastern (MID) AF: 0.783 AC: 224 AN: 286

European-Non Finnish (NFE) AF: 0.892 AC: 59099 AN: 66274

Other (OTH) AF: 0.879 AC: 1817 AN: 2066

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 04, 2018

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	-0.79
CADD	Benign	18
DANN	Benign	0.80
PhyloP100		0.59
PromoterAI		-0.014	Neutral
Mutation Taster		=292/8	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: rs188660514; hg19: chr18-33877687;