chr5-33984498-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016180.5(SLC45A2):c.86A>C(p.Lys29Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K29R) has been classified as Uncertain significance.

Frequency

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

Consequence

SLC45A2
NM_016180.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0140

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

oculocutaneous albinism type 4
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P

SLC45A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12622222).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016180.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC45A2	NM_016180.5	MANE Select	c.86A>C	p.Lys29Thr	missense	Exon 1 of 7	NP_057264.4
SLC45A2	NM_001012509.4		c.86A>C	p.Lys29Thr	missense	Exon 1 of 6	NP_001012527.2
SLC45A2	NM_001297417.4		c.86A>C	p.Lys29Thr	missense	Exon 1 of 4	NP_001284346.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC45A2	ENST00000296589.9	TSL:1 MANE Select	c.86A>C	p.Lys29Thr	missense	Exon 1 of 7	ENSP00000296589.4
SLC45A2	ENST00000382102.7	TSL:1	c.86A>C	p.Lys29Thr	missense	Exon 1 of 6	ENSP00000371534.3
SLC45A2	ENST00000509381.1	TSL:1	c.86A>C	p.Lys29Thr	missense	Exon 1 of 4	ENSP00000421100.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250458

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 29 of the SLC45A2 protein (p.Lys29Thr). This variant is present in population databases (rs199882086, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SLC45A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1444885). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SLC45A2 protein function with a negative predictive value of 80%. 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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.47

CADD

Benign

7.6

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.020

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

PhyloP100

-0.014

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.2

REVEL

Benign

0.038

Sift

Uncertain

0.011

Sift4G

Uncertain

0.014

Polyphen

0.037

Vest4

0.26

MutPred

0.34

Loss of methylation at K29 (P = 0.0097)

MVP

0.33

MPC

0.11

ClinPred

0.66

GERP RS

-0.072

PromoterAI

0.017

Neutral

(source)

Varity_R

0.11

gMVP

0.49

Mutation Taster

=84/16

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over