3-46860639-T-G

Variant names:

• chr3-46860639-T-G
• rs2227294
• NM_000258.3:c.307+37A>C

Variant summary

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

The NM_000258.3(MYL3):​c.307+37A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,609,092 control chromosomes in the GnomAD database, including 48,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (14755 hom., cov: 32)
  • Exomes 𝑓: 0.17 (33888 hom.)
• Consequence: MYL3 NM_000258.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.260
• Publications: 9 publications found

Genes affected

MYL3 (HGNC:7584): (myosin light chain 3) MYL3 encodes myosin light chain 3, an alkali light chain also referred to in the literature as both the ventricular isoform and the slow skeletal muscle isoform. Mutations in MYL3 have been identified as a cause of mid-left ventricular chamber type hypertrophic cardiomyopathy. [provided by RefSeq, Jul 2008]

MYL3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 8

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-46860639-T-G is Benign according to our data. Variant chr3-46860639-T-G is described in ClinVar as [Benign]. Clinvar id is 255638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL3	NM_000258.3	c.307+37A>C		intron_variant	Intron 3 of 6	ENST00000292327.6	NP_000249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6	c.307+37A>C		intron_variant	Intron 3 of 6	1	NM_000258.3	ENSP00000292327.4

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51348 AN: 151966 Hom.: 14710 Cov.: 32

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.300

GnomAD2 exomes AF: 0.253 AC: 62292 AN: 246266 AF XY: 0.245

Gnomad AFR exome AF: 0.785

Gnomad AMR exome AF: 0.323

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.379

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.170 AC: 247368 AN: 1457008 Hom.: 33888 Cov.: 34 AF XY: 0.174 AC XY: 126456 AN XY: 724998

African (AFR) AF: 0.799 AC: 26715 AN: 33450

American (AMR) AF: 0.318 AC: 14201 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5972 AN: 26122

East Asian (EAS) AF: 0.376 AC: 14916 AN: 39682

South Asian (SAS) AF: 0.400 AC: 34443 AN: 86186

European-Finnish (FIN) AF: 0.134 AC: 6675 AN: 49740

Middle Eastern (MID) AF: 0.285 AC: 1482 AN: 5200

European-Non Finnish (NFE) AF: 0.117 AC: 130149 AN: 1111692

Other (OTH) AF: 0.213 AC: 12815 AN: 60282

GnomAD4 genome AF: 0.338 AC: 51450 AN: 152084 Hom.: 14755 Cov.: 32 AF XY: 0.340 AC XY: 25311 AN XY: 74356

African (AFR) AF: 0.775 AC: 32126 AN: 41468

American (AMR) AF: 0.271 AC: 4142 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 784 AN: 3462

East Asian (EAS) AF: 0.375 AC: 1937 AN: 5164

South Asian (SAS) AF: 0.411 AC: 1976 AN: 4812

European-Finnish (FIN) AF: 0.140 AC: 1486 AN: 10598

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8100 AN: 67974

Other (OTH) AF: 0.299 AC: 630 AN: 2106

Alfa AF: 0.182 Hom.: 10617

Bravo AF: 0.368

Asia WGS AF: 0.371 AC: 1288 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 8 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.6
DANN	Benign	0.33
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2227294; hg19: chr3-46902129; COSMIC: COSV52767695; COSMIC: COSV52767695;