rs727505358

Variant names:

• chr14-23390216-G-A
• rs727505358
• NM_002471.4:c.3573C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002471.4(MYH6):​c.3573C>T​(p.Ala1191Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,596,748 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00056 (4 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.63
• Publications: 2 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):

• MYH-6 related congenital heart defects

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 14-23390216-G-A is Benign according to our data. Variant chr14-23390216-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 180116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00056 (85/151842) while in subpopulation NFE AF = 0.000928 (63/67908). AF 95% confidence interval is 0.000743. There are 1 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 85 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002471.4. 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
	MYH6	NM_002471.4	MANE Select	c.3573C>T	p.Ala1191Ala	synonymous	Exon 26 of 39	NP_002462.2	P13533

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.3573C>T	p.Ala1191Ala	synonymous	Exon 26 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.3606C>T	p.Ala1202Ala	synonymous	Exon 26 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3573C>T	p.Ala1191Ala	synonymous	Exon 26 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.000547 AC: 83 AN: 151724 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000663

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000913

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.000633 AC: 146 AN: 230572 AF XY: 0.000665

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000423

Gnomad ASJ exome AF: 0.000625

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000737

Gnomad NFE exome AF: 0.000843

Gnomad OTH exome AF: 0.00106

GnomAD4 exome AF: 0.000562 AC: 812 AN: 1444906 Hom.: 4 Cov.: 34 AF XY: 0.000583 AC XY: 418 AN XY: 717528

African (AFR) AF: 0.0000906 AC: 3 AN: 33096

American (AMR) AF: 0.000390 AC: 17 AN: 43546

Ashkenazi Jewish (ASJ) AF: 0.000540 AC: 14 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39284

South Asian (SAS) AF: 0.000549 AC: 47 AN: 85564

European-Finnish (FIN) AF: 0.000876 AC: 46 AN: 52534

Middle Eastern (MID) AF: 0.00657 AC: 27 AN: 4108

European-Non Finnish (NFE) AF: 0.000554 AC: 610 AN: 1101320

Other (OTH) AF: 0.000806 AC: 48 AN: 59542

GnomAD4 genome AF: 0.000560 AC: 85 AN: 151842 Hom.: 1 Cov.: 31 AF XY: 0.000499 AC XY: 37 AN XY: 74206

African (AFR) AF: 0.0000483 AC: 2 AN: 41406

American (AMR) AF: 0.000262 AC: 4 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4788

European-Finnish (FIN) AF: 0.000663 AC: 7 AN: 10566

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000928 AC: 63 AN: 67908

Other (OTH) AF: 0.000477 AC: 1 AN: 2098

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000468

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.4
DANN	Benign	0.94
PhyloP100		-1.6
Mutation Taster		=99/1	polymorphism

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: rs727505358; hg19: chr14-23859425;