chr5-33944709-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3PP5

The NM_016180.5(SLC45A2):​c.1532C>T​(p.Ala511Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,090 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A511E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SLC45A2
NM_016180.5 missense

Scores

8
9
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.64
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 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
PM5
Other missense variant is known to change same aminoacid residue: Variant chr5-33944709-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2203615.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.827
PP5
Variant 5-33944709-G-A is Pathogenic according to our data. Variant chr5-33944709-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 617813.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC45A2NM_016180.5 linkuse as main transcriptc.1532C>T p.Ala511Val missense_variant 7/7 ENST00000296589.9
SLC45A2XM_047417259.1 linkuse as main transcriptc.1292C>T p.Ala431Val missense_variant 7/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC45A2ENST00000296589.9 linkuse as main transcriptc.1532C>T p.Ala511Val missense_variant 7/71 NM_016180.5 P1Q9UMX9-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152200
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251330
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.0000616
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:
0.00000479
AC:
7
AN:
1461890
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152200
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.000145
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000222
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 12, 2020The sequence change, c.1532C>T, in exon 7 results in an amino acid change, p.Ala511Val. The p.Ala511Val change affects a highly conserved amino acid residue located in a domain of the SLC45A2 protein that is known to be functional. The p.Ala511Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Mutation Taster, REVEL). This particular amino acid change has been described in Pakistani consanguineous families with oculocutaneous albinism in the homozygous state (PMIDs: 28266639, 30868578). This sequence change has been described in the gnomAD database in three heterozygous individuals which corresponds to a population frequency of 0.0011% (dbSNP rs748872789); however, it has not been observed in homozygous state in any individuals. These collective evidences indicate that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively. -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeFeb 05, 2022This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 511 of the SLC45A2 protein (p.Ala511Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of oculocutaneous albinism (PMID: 30868578). ClinVar contains an entry for this variant (Variation ID: 617813). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Ala511 amino acid residue in SLC45A2. Other variant(s) that disrupt this residue have been observed in individuals with SLC45A2-related conditions (PMID: 18821858), which suggests that this may be a clinically significant amino acid residue. 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. -
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJan 12, 2021This variant is associated with the following publications: (PMID: 31589614, 23190901, 32221475, 31229681, 30868578, 28266639) -
Nonsyndromic Oculocutaneous Albinism Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of WashingtonMar 07, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.84
D
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D
M_CAP
Benign
0.060
D
MetaRNN
Pathogenic
0.83
D
MetaSVM
Uncertain
0.76
D
MutationAssessor
Pathogenic
3.3
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-3.3
D
REVEL
Uncertain
0.61
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
0.66
MutPred
0.54
Gain of sheet (P = 0.0827);
MVP
0.91
MPC
0.27
ClinPred
0.96
D
GERP RS
5.7
Varity_R
0.48
gMVP
0.77

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: rs748872789; hg19: chr5-33944814; COSMIC: COSV56870631; COSMIC: COSV56870631; API