12-55955821-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001384361.1(PMEL):c.1514G>A(p.Gly505Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. G505S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PMEL
NM_001384361.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.22

Variant links:

Genes affected

PMEL (HGNC:10880): (premelanosome protein) This gene encodes a melanocyte-specific type I transmembrane glycoprotein. The encoded protein is enriched in melanosomes, which are the melanin-producing organelles in melanocytes, and plays an essential role in the structural organization of premelanosomes. This protein is involved in generating internal matrix fibers that define the transition from Stage I to Stage II melanosomes. This protein undergoes a complex pattern of prosttranslational processing and modification that is essential to the proper functioning of the protein. A secreted form of this protein that is released by proteolytic ectodomain shedding may be used as a melanoma-specific serum marker. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2011]

PMEL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13687238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMEL	NM_001384361.1 linkuse as main transcript	c.1514G>A	p.Gly505Asp	missense_variant	8/11	ENST00000548747.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMEL	ENST00000548747.6 linkuse as main transcript	c.1514G>A	p.Gly505Asp	missense_variant	8/11	1	NM_001384361.1	P4	P40967-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152228

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251454

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135910

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727224

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:

0.0000171

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2021

The c.1514G>A (p.G505D) alteration is located in exon 8 (coding exon 8) of the PMEL gene. This alteration results from a G to A substitution at nucleotide position 1514, causing the glycine (G) at amino acid position 505 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.087

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.70

T;.;T;.;T;T

M_CAP

Benign

0.0084

MetaRNN

Benign

0.14

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N;.;N;N;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.2

N;N;N;N;N;N

REVEL

Benign

0.092

Sift

Benign

0.041

D;T;T;T;T;T

Sift4G

Benign

0.080

T;T;T;T;T;T

Polyphen

0.13

B;B;B;B;B;.

Vest4

0.28

MutPred

0.36

Gain of catalytic residue at G507 (P = 0.0151);Gain of catalytic residue at G507 (P = 0.0151);.;Gain of catalytic residue at G507 (P = 0.0151);Gain of catalytic residue at G507 (P = 0.0151);.;

MVP

0.22

MPC

0.18

ClinPred

0.35

GERP RS

5.6

Varity_R

0.20

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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