rs439735

Variant names:

• chr14-23399076-G-A
• rs439735
• NM_002471.4:c.1582-39C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002471.4(MYH6):​c.1582-39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,608,864 control chromosomes in the GnomAD database, including 49,114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.22 (4079 hom., cov: 31)
  • Exomes 𝑓: 0.24 (45035 hom.)
• Consequence: MYH6 NM_002471.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0950
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-23399076-G-A is Benign according to our data. Variant chr14-23399076-G-A is described in ClinVar as Benign. ClinVar VariationId is 258706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.1582-39C>T		intron_variant	Intron 14 of 38	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.1582-39C>T		intron_variant	Intron 14 of 38	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34122 AN: 151824 Hom.: 4081 Cov.: 31

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.0658

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.227

GnomAD2 exomes AF: 0.210 AC: 52154 AN: 248560 AF XY: 0.214

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.0664

Gnomad FIN exome AF: 0.216

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.244 AC: 355222 AN: 1456922 Hom.: 45035 Cov.: 32 AF XY: 0.243 AC XY: 175981 AN XY: 725090

African (AFR) AF: 0.190 AC: 6346 AN: 33374

American (AMR) AF: 0.136 AC: 6077 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 7936 AN: 26108

East Asian (EAS) AF: 0.0524 AC: 2078 AN: 39674

South Asian (SAS) AF: 0.195 AC: 16806 AN: 86162

European-Finnish (FIN) AF: 0.220 AC: 11710 AN: 53342

Middle Eastern (MID) AF: 0.219 AC: 1209 AN: 5518

European-Non Finnish (NFE) AF: 0.261 AC: 288706 AN: 1107902

Other (OTH) AF: 0.239 AC: 14354 AN: 60174

GnomAD4 genome AF: 0.225 AC: 34134 AN: 151942 Hom.: 4079 Cov.: 31 AF XY: 0.222 AC XY: 16516 AN XY: 74270

African (AFR) AF: 0.191 AC: 7929 AN: 41454

American (AMR) AF: 0.200 AC: 3051 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1058 AN: 3468

East Asian (EAS) AF: 0.0662 AC: 342 AN: 5168

South Asian (SAS) AF: 0.184 AC: 886 AN: 4810

European-Finnish (FIN) AF: 0.214 AC: 2257 AN: 10542

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17718 AN: 67918

Other (OTH) AF: 0.225 AC: 475 AN: 2112

Alfa AF: 0.227 Hom.: 2329

Bravo AF: 0.219

Asia WGS AF: 0.126 AC: 438 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.5
DANN	Benign	0.64
PhyloP100		-0.095
BranchPoint Hunter		2.0
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: rs439735; hg19: chr14-23868285;