17-47209492-G-T

Variant names:

• chr17-47209492-G-T
• rs1157307211
• NM_002476.2:c.70G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002476.2(MYL4):​c.70G>T​(p.Ala24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A24A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYL4 NM_002476.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.813

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08698583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL4	NM_002476.2	c.70G>T	p.Ala24Ser	missense_variant	Exon 1 of 7	ENST00000393450.5	NP_002467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL4	ENST00000393450.5	c.70G>T	p.Ala24Ser	missense_variant	Exon 1 of 7	1	NM_002476.2	ENSP00000377096.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrial fibrillation, familial, 18 Uncertain:1

Oct 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 24 of the MYL4 protein (p.Ala24Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYL4-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	Benign	0.12
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.32	T;T;T;.;T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.72	.;T;T;T;.;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.087	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M;M;.;.;M;.
PhyloP100		0.81
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.79	.;N;.;.;N;.
REVEL	Benign	0.049
Sift	Benign	0.35	.;T;.;.;T;.
Sift4G	Benign	0.23	T;T;T;T;T;T
Polyphen		0.079	B;B;.;.;B;.
Vest4		0.25
MutPred		0.28		Gain of phosphorylation at A24 (P = 3e-04);Gain of phosphorylation at A24 (P = 3e-04);Gain of phosphorylation at A24 (P = 3e-04);Gain of phosphorylation at A24 (P = 3e-04);Gain of phosphorylation at A24 (P = 3e-04);Gain of phosphorylation at A24 (P = 3e-04);
MVP		0.65
MPC		0.14
ClinPred		0.095	T
GERP RS		2.7
PromoterAI		0.0039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
gMVP		0.38

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

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Other links and lift over

dbSNP: rs1157307211; hg19: chr17-45286858;