rs121912619

Positions:

chr5-33951628-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP5

The NM_016180.5(SLC45A2):c.1082T>C(p.Leu361Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L361L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

SLC45A2
NM_016180.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 2.25

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]

SLC45A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a topological_domain Extracellular (size 26) in uniprot entity S45A2_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_016180.5

PP5

Variant 5-33951628-A-G is Pathogenic according to our data. Variant chr5-33951628-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4499.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr5-33951628-A-G is described in Lovd as [Likely_pathogenic]. Variant chr5-33951628-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC45A2	NM_016180.5 linkuse as main transcript	c.1082T>C	p.Leu361Pro	missense_variant	5/7	ENST00000296589.9
SLC45A2	NM_001012509.4 linkuse as main transcript	c.1082T>C	p.Leu361Pro	missense_variant	5/6
SLC45A2	XM_047417259.1 linkuse as main transcript	c.842T>C	p.Leu281Pro	missense_variant	5/7
SLC45A2	NM_001297417.4 linkuse as main transcript	c.*24T>C		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC45A2	ENST00000296589.9 linkuse as main transcript	c.1082T>C	p.Leu361Pro	missense_variant	5/7	1	NM_016180.5	P1	Q9UMX9-1
SLC45A2	ENST00000382102.7 linkuse as main transcript	c.1082T>C	p.Leu361Pro	missense_variant	5/6	1			Q9UMX9-4
SLC45A2	ENST00000509381.1 linkuse as main transcript	c.*24T>C		3_prime_UTR_variant	4/4	1
SLC45A2	ENST00000510600.1 linkuse as main transcript	c.557T>C	p.Leu186Pro	missense_variant	4/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152212

Hom.:

Cov.:

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251472

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135912

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:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727244

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:

0.0000414

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74360

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:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000949

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 361 of the SLC45A2 protein (p.Leu361Pro). This variant is present in population databases (rs121912619, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of oculocutaneous albinism (PMID: 14722913, 29345414, 34078970; 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: 4499). 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 not expected to disrupt SLC45A2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Oculocutaneous albinism type 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.82

T;T;T

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.66

D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.3

M;M;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.0

N;N;N

REVEL

Pathogenic

0.70

Sift

Benign

0.24

T;T;T

Sift4G

Benign

0.38

T;T;D

Polyphen

0.85

P;P;.

Vest4

0.90

MVP

0.94

MPC

0.23

ClinPred

0.44

GERP RS

5.9

Varity_R

0.61

gMVP

0.97

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over