14-23389062-A-T

Variant names:

• chr14-23389062-A-T
• rs535111647
• NM_002471.4:c.3979-7T>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000405093.9(MYH6):​c.3979-7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000078 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00097 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 ENST00000405093.9 splice_region, intron
• Scores: Splicing: ADA: 0.01137
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.588
• Publications: 0 publications found

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

MYH6 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
• Keppen-Lubinsky syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atrial septal defect 3

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000405093.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.3979-7T>A		splice_region intron	N/A	NP_002462.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.3979-7T>A		splice_region intron	N/A	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.0000778 AC: 9 AN: 115618 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000355

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000657

Gnomad SAS AF: 0.000291

Gnomad FIN AF: 0.000141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000968 AC: 1025 AN: 1058436 Hom.: 0 Cov.: 27 AF XY: 0.000857 AC XY: 452 AN XY: 527482

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30382

American (AMR) AF: 0.000203 AC: 6 AN: 29548

Ashkenazi Jewish (ASJ) AF: 0.000775 AC: 15 AN: 19364

East Asian (EAS) AF: 0.00126 AC: 35 AN: 27730

South Asian (SAS) AF: 0.000153 AC: 10 AN: 65506

European-Finnish (FIN) AF: 0.000171 AC: 6 AN: 35002

Middle Eastern (MID) AF: 0.000715 AC: 3 AN: 4194

European-Non Finnish (NFE) AF: 0.00113 AC: 909 AN: 801604

Other (OTH) AF: 0.000909 AC: 41 AN: 45106

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000778 AC: 9 AN: 115732 Hom.: 0 Cov.: 26 AF XY: 0.0000352 AC XY: 2 AN XY: 56878

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000257 AC: 1 AN: 38886

American (AMR) AF: 0.000354 AC: 4 AN: 11284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2598

East Asian (EAS) AF: 0.000659 AC: 2 AN: 3034

South Asian (SAS) AF: 0.000291 AC: 1 AN: 3434

European-Finnish (FIN) AF: 0.000141 AC: 1 AN: 7100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 46888

Other (OTH) AF: 0.00 AC: 0 AN: 1590

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.9
DANN	Benign	0.83
PhyloP100		-0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.070		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: rs535111647; hg19: chr14-23858271;