rs3729820

Variant names:

• chr14-23419162-G-A
• rs3729820
• NM_000257.4:c.3972+15C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-23419162-G-A
• chr14-23419162-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000257.4(MYH7):​c.3972+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,612,430 control chromosomes in the GnomAD database, including 214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 32)
  • Exomes 𝑓: 0.014 (196 hom.)
• Consequence: MYH7 NM_000257.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -1.04
• Publications: 2 publications found

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

MYH7 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-23419162-G-A is Benign according to our data. Variant chr14-23419162-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0112 (1701/152322) while in subpopulation NFE AF = 0.0161 (1098/68018). AF 95% confidence interval is 0.0153. There are 18 homozygotes in GnomAd4. There are 872 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000257.4. 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
	MYH7	NM_000257.4	MANE Select	c.3972+15C>T		intron	N/A	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.3972+15C>T		intron	N/A	NP_001393933.1	P12883

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.3972+15C>T		intron	N/A	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.3972+15C>T		intron	N/A	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.3972+15C>T		intron	N/A	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1701 AN: 152204 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.0117 AC: 2952 AN: 251426 AF XY: 0.0119

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0331

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0139 AC: 20306 AN: 1460108 Hom.: 196 Cov.: 33 AF XY: 0.0140 AC XY: 10143 AN XY: 726542

African (AFR) AF: 0.00236 AC: 79 AN: 33434

American (AMR) AF: 0.00224 AC: 100 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00482 AC: 126 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00813 AC: 701 AN: 86220

European-Finnish (FIN) AF: 0.0325 AC: 1734 AN: 53374

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.0152 AC: 16875 AN: 1110428

Other (OTH) AF: 0.0113 AC: 682 AN: 60344

GnomAD4 genome AF: 0.0112 AC: 1701 AN: 152322 Hom.: 18 Cov.: 32 AF XY: 0.0117 AC XY: 872 AN XY: 74492

African (AFR) AF: 0.00228 AC: 95 AN: 41580

American (AMR) AF: 0.00627 AC: 96 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00579 AC: 28 AN: 4834

European-Finnish (FIN) AF: 0.0332 AC: 352 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0161 AC: 1098 AN: 68018

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.0130 Hom.: 7

Bravo AF: 0.00812

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Hypertrophic cardiomyopathy 1 (1)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)
-	-	1	MYH7-related skeletal myopathy (1)
-	-	1	Myosin storage myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.41
PhyloP100		-1.0
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: rs3729820; hg19: chr14-23888371;