17-47221786-C-T

Variant names:

• chr17-47221786-C-T
• rs767035280
• NM_002476.2:c.418C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_002476.2(MYL4):​c.418C>T​(p.Arg140Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: MYL4 NM_002476.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

Genes affected

MYL4 (HGNC:7585): (myosin light chain 4) Myosin is a hexameric ATPase cellular motor protein. It is composed of two myosin heavy chains, two nonphosphorylatable myosin alkali light chains, and two phosphorylatable myosin regulatory light chains. This gene encodes a myosin alkali light chain that is found in embryonic muscle and adult atria. Two alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL4	NM_002476.2	c.418C>T	p.Arg140Cys	missense_variant	Exon 4 of 7	ENST00000393450.5	NP_002467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL4	ENST00000393450.5	c.418C>T	p.Arg140Cys	missense_variant	Exon 4 of 7	1	NM_002476.2	ENSP00000377096.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251408 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135882

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74318

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrial fibrillation, familial, 18 Uncertain:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 140 of the MYL4 protein (p.Arg140Cys). This variant is present in population databases (rs767035280, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 542788). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;D;D;.;D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	.;D;D;D;.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	M;M;.;.;M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.3	.;D;.;.;D;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;D;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;D;.
Vest4		0.85
MVP		0.96
MPC		0.77
ClinPred		0.76	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.81
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs767035280; hg19: chr17-45299152; COSMIC: COSV100733195;