4-681930-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002477.2(MYL5):c.458C>T(p.Ala153Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,325,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A153P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: MYL5 NM_002477.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

Genes affected

MYL5 (HGNC:7586): (myosin light chain 5) This gene encodes one of the myosin light chains, a component of the hexameric ATPase cellular motor protein myosin. Myosin is composed of two heavy chains, two nonphosphorylatable alkali light chains, and two phosphorylatable regulatory light chains. This gene product, one of the regulatory light chains, is expressed in fetal muscle and in adult retina, cerebellum, and basal ganglia. [provided by RefSeq, Jul 2008]

SLC49A3 (HGNC:26177): (solute carrier family 49 member 3) Predicted to enable transmembrane transporter activity. Predicted to be involved in transmembrane transport. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10435128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL5	NM_002477.2	c.458C>T	p.Ala153Val	missense_variant	9/9	ENST00000400159.7
SLC49A3	NM_032219.4	c.*28G>A		3_prime_UTR_variant	10/10	ENST00000322224.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL5	ENST00000400159.7	c.458C>T	p.Ala153Val	missense_variant	9/9	1	NM_002477.2	P1
SLC49A3	ENST00000322224.9	c.*28G>A		3_prime_UTR_variant	10/10	1	NM_032219.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000856 AC: 13 AN: 151948 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000150 AC: 17 AN: 113312 Hom.: 0 AF XY: 0.000179 AC XY: 11 AN XY: 61288

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000266

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000191 AC: 224 AN: 1173876 Hom.: 0 Cov.: 31 AF XY: 0.000223 AC XY: 126 AN XY: 565028

Gnomad4 AFR exome AF: 0.0000802

Gnomad4 AMR exome AF: 0.000230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000985

Gnomad4 SAS exome AF: 0.000231

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.0000857

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.000143 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.458C>T (p.A153V) alteration is located in exon 7 (coding exon 7) of the MYL5 gene. This alteration results from a C to T substitution at nucleotide position 458, causing the alanine (A) at amino acid position 153 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Uncertain	0.99
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.47	N
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	D;D;D;D;D;N;N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.081
Sift	Benign	0.088	T;T;T;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.23	.;.;.;B
Vest4		0.23
MutPred		0.42		.;.;.;Loss of helix (P = 0.2022);
MVP		0.56
MPC		0.032
ClinPred		0.051	T
GERP RS		2.5
Varity_R		0.047
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs552967269; hg19: chr4-675719;