18-36298120-C-T

Variant names:

• chr18-36298120-C-T
• rs4438379
• NM_001281740.3:c.165+120C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001281740.3(FHOD3):​c.165+120C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 875,096 control chromosomes in the GnomAD database, including 59,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (8160 hom., cov: 31)
  • Exomes 𝑓: 0.36 (51258 hom.)
• Consequence: FHOD3 NM_001281740.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.40
• Publications: 1 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):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, ClinGen
• cardiomyopathy, familial hypertrophic, 28

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 18-36298120-C-T is Benign according to our data. Variant chr18-36298120-C-T is described in ClinVar as Benign. ClinVar VariationId is 1233999.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001281740.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHOD3	NM_001281740.3	MANE Select	c.165+120C>T		intron	N/A	NP_001268669.1	Q2V2M9-4
	FHOD3	NM_025135.5		c.165+120C>T		intron	N/A	NP_079411.2
	FHOD3	NM_001281739.3		c.165+120C>T		intron	N/A	NP_001268668.1	Q2V2M9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHOD3	ENST00000590592.6	TSL:1 MANE Select	c.165+120C>T		intron	N/A	ENSP00000466937.1	Q2V2M9-4
	FHOD3	ENST00000257209.8	TSL:1	c.165+120C>T		intron	N/A	ENSP00000257209.3	Q2V2M9-3
	FHOD3	ENST00000359247.8	TSL:1	c.165+120C>T		intron	N/A	ENSP00000352186.3	Q2V2M9-1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46181 AN: 151518 Hom.: 8156 Cov.: 31

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.00275

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.288

GnomAD4 exome AF: 0.357 AC: 258033 AN: 723470 Hom.: 51258 AF XY: 0.350 AC XY: 126459 AN XY: 361260

African (AFR) AF: 0.168 AC: 2415 AN: 14390

American (AMR) AF: 0.292 AC: 2332 AN: 7992

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 3103 AN: 13174

East Asian (EAS) AF: 0.000657 AC: 16 AN: 24358

South Asian (SAS) AF: 0.136 AC: 5159 AN: 37986

European-Finnish (FIN) AF: 0.452 AC: 15257 AN: 33748

Middle Eastern (MID) AF: 0.225 AC: 529 AN: 2350

European-Non Finnish (NFE) AF: 0.393 AC: 218594 AN: 556096

Other (OTH) AF: 0.318 AC: 10628 AN: 33376

GnomAD4 genome AF: 0.305 AC: 46216 AN: 151626 Hom.: 8160 Cov.: 31 AF XY: 0.299 AC XY: 22127 AN XY: 74056

African (AFR) AF: 0.186 AC: 7686 AN: 41402

American (AMR) AF: 0.279 AC: 4263 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 824 AN: 3470

East Asian (EAS) AF: 0.00275 AC: 14 AN: 5082

South Asian (SAS) AF: 0.124 AC: 597 AN: 4818

European-Finnish (FIN) AF: 0.452 AC: 4758 AN: 10532

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.398 AC: 26960 AN: 67744

Other (OTH) AF: 0.285 AC: 602 AN: 2110

Alfa AF: 0.359 Hom.: 1768

Bravo AF: 0.290

Asia WGS AF: 0.0770 AC: 270 AN: 3462

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		1.4
PromoterAI		-0.0098	Neutral
Mutation Taster		=100/0	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: rs4438379; hg19: chr18-33878083;