15-52317044-C-T

Variant names:

• chr15-52317044-C-T
• rs72734962
• NM_001382347.1:c.5409+4G>A

Variant summary

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

The NM_001382347.1(MYO5A):​c.5409+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00905 in 1,613,148 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (82 hom.)
• Consequence: MYO5A NM_001382347.1 splice_region, intron
• Scores: Splicing: ADA: 0.0002138
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.367

Genes affected

MYO5A (HGNC:7602): (myosin VA) This gene is one of three myosin V heavy-chain genes, belonging to the myosin gene superfamily. Myosin V is a class of actin-based motor proteins involved in cytoplasmic vesicle transport and anchorage, spindle-pole alignment and mRNA translocation. The protein encoded by this gene is abundant in melanocytes and nerve cells. Mutations in this gene cause Griscelli syndrome type-1 (GS1) and neuroectodermal melanolysosomal disease, or Elejalde disease. [provided by RefSeq, Sep 2023]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 15-52317044-C-T is Benign according to our data. Variant chr15-52317044-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 211572.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 = 0.0065 (990/152284) while in subpopulation NFE AF = 0.0107 (727/68008). AF 95% confidence interval is 0.01. There are 15 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO5A	NM_001382347.1	c.5409+4G>A		splice_region_variant, intron_variant	Intron 40 of 41	ENST00000399233.7	NP_001369276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO5A	ENST00000399233.7	c.5409+4G>A		splice_region_variant, intron_variant	Intron 40 of 41	5	NM_001382347.1	ENSP00000382179.4

Frequencies

GnomAD3 genomes AF: 0.00650 AC: 989 AN: 152166 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.00321

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00678 AC: 1690 AN: 249400 AF XY: 0.00699

Gnomad AFR exome AF: 0.00213

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00343

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.00727

GnomAD4 exome AF: 0.00932 AC: 13611 AN: 1460864 Hom.: 82 Cov.: 31 AF XY: 0.00913 AC XY: 6638 AN XY: 726800

Gnomad4 AFR exome AF: 0.00194 AC: 65 AN: 33454

Gnomad4 AMR exome AF: 0.00353 AC: 158 AN: 44722

Gnomad4 ASJ exome AF: 0.000115 AC: 3 AN: 26124

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39678

Gnomad4 SAS exome AF: 0.00649 AC: 560 AN: 86236

Gnomad4 FIN exome AF: 0.00360 AC: 192 AN: 53406

Gnomad4 NFE exome AF: 0.0108 AC: 12047 AN: 1111124

Gnomad4 Remaining exome AF: 0.00916 AC: 553 AN: 60358

GnomAD4 genome AF: 0.00650 AC: 990 AN: 152284 Hom.: 15 Cov.: 32 AF XY: 0.00661 AC XY: 492 AN XY: 74458

Gnomad4 AFR AF: 0.00164 AC: 0.00163572 AN: 0.00163572

Gnomad4 AMR AF: 0.00517 AC: 0.00516542 AN: 0.00516542

Gnomad4 ASJ AF: 0.000865 AC: 0.000865052 AN: 0.000865052

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00767 AC: 0.00767316 AN: 0.00767316

Gnomad4 FIN AF: 0.00321 AC: 0.00320513 AN: 0.00320513

Gnomad4 NFE AF: 0.0107 AC: 0.0106899 AN: 0.0106899

Gnomad4 OTH AF: 0.00473 AC: 0.00473037 AN: 0.00473037

Alfa AF: 0.00883 Hom.: 4

Bravo AF: 0.00674

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.0109

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO5A: BP4, BS1, BS2 -

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 22, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Aug 04, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Griscelli syndrome type 1 Benign:1

Jul 25, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 1% (727/68016) including 11 homozygotes (https://gnomad.broadinstitute.org/variant/15-52317044-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with multiple labs classifying this variant as Benign (Variation ID:211572). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Splice prediction tools do not suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.49
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.022
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: rs72734962; hg19: chr15-52609241;