chr5-33944703-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP5_Moderate

The NM_016180.5(SLC45A2):​c.1538C>A​(p.Ala513Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A513A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SLC45A2
NM_016180.5 missense

Scores

7
12

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.51
Variant links:
Genes affected
SLC45A2 (HGNC:16472): (solute carrier family 45 member 2) This gene encodes a transporter protein that mediates melanin synthesis. The protein is expressed in a high percentage of melanoma cell lines. Mutations in this gene are a cause of oculocutaneous albinism type 4, and polymorphisms in this gene are associated with variations in skin and hair color. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_016180.5
PP5
Variant 5-33944703-G-T is Pathogenic according to our data. Variant chr5-33944703-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1365427.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC45A2NM_016180.5 linkuse as main transcriptc.1538C>A p.Ala513Glu missense_variant 7/7 ENST00000296589.9
SLC45A2XM_047417259.1 linkuse as main transcriptc.1298C>A p.Ala433Glu missense_variant 7/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC45A2ENST00000296589.9 linkuse as main transcriptc.1538C>A p.Ala513Glu missense_variant 7/71 NM_016180.5 P1Q9UMX9-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251300
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135834
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461894
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 16, 2024This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 513 of the SLC45A2 protein (p.Ala513Glu). This variant is present in population databases (rs373846997, gnomAD no frequency). This missense change has been observed in individual(s) with oculocutaneous albinism (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1365427). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC45A2 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Uncertain
0.039
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
13
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.56
D
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.49
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.77
T
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.45
T
MetaSVM
Benign
-0.44
T
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-2.0
N
REVEL
Uncertain
0.56
Sift
Benign
0.031
D
Sift4G
Benign
0.14
T
Polyphen
0.69
P
Vest4
0.48
MVP
0.87
MPC
0.13
ClinPred
0.28
T
GERP RS
0.95
Varity_R
0.10
gMVP
0.62

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs373846997; hg19: chr5-33944808; API