chr5-33944686-A-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_ModeratePP5_Moderate
The NM_016180.5(SLC45A2):āc.1555T>Cā(p.Cys519Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,614,102 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 Likely pathogenic (ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 33)
Exomes š: 0.000031 ( 0 hom. )
Consequence
SLC45A2
NM_016180.5 missense
NM_016180.5 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 7.09
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 Likely_pathogenic. Variant got 6 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
PP3
MetaRNN computational evidence supports a deleterious effect, 0.922
PP5
Variant 5-33944686-A-G is Pathogenic according to our data. Variant chr5-33944686-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1939785.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC45A2 | NM_016180.5 | c.1555T>C | p.Cys519Arg | missense_variant | 7/7 | ENST00000296589.9 | |
SLC45A2 | XM_047417259.1 | c.1315T>C | p.Cys439Arg | missense_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC45A2 | ENST00000296589.9 | c.1555T>C | p.Cys519Arg | missense_variant | 7/7 | 1 | NM_016180.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152216Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251354Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135870
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GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727246
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74372
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 519 of the SLC45A2 protein (p.Cys519Arg). This variant is present in population databases (rs750510834, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of 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: 1939785). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of methylation at C519 (P = 0.0296);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at