Variant 5-33964001-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3PP5_Moderate

The NM_016180.5(SLC45A2):c.578T>G(p.Leu193Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,238 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 (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

SLC45A2
NM_016180.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.07

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_016180.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

PP5

Variant 5-33964001-A-C is Pathogenic according to our data. Variant chr5-33964001-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212206.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-33964001-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC45A2	NM_016180.5 linkuse as main transcript	c.578T>G	p.Leu193Arg	missense_variant	3/7	ENST00000296589.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC45A2	ENST00000296589.9 linkuse as main transcript	c.578T>G	p.Leu193Arg	missense_variant	3/7	1	NM_016180.5	P1	Q9UMX9-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

Bravo

AF:

0.0000113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Oculocutaneous albinism type 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.084

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.6

M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.055

T;T;D

Polyphen

0.81

P;P;.

Vest4

0.87

MutPred

0.70

Gain of methylation at L193 (P = 0.0017);Gain of methylation at L193 (P = 0.0017);.;

MVP

0.93

MPC

0.29

ClinPred

1.0

GERP RS

5.9

Varity_R

0.92

gMVP

0.87

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