Variant 12-55957383-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001384361.1(PMEL):c.920C>A(p.Pro307Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,446,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P307T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PMEL
NM_001384361.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.62

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36903584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMEL	NM_001384361.1 linkuse as main transcript	c.920C>A	p.Pro307Gln	missense_variant	6/11	ENST00000548747.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMEL	ENST00000548747.6 linkuse as main transcript	c.920C>A	p.Pro307Gln	missense_variant	6/11	1	NM_001384361.1	P4	P40967-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000126

AC:

AN:

238822

Hom.:

AF XY:

0.00000779

AC XY:

AN XY:

128416

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1446032

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717324

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Nov 17, 2023

The c.920C>A (p.P307Q) alteration is located in exon 6 (coding exon 6) of the PMEL gene. This alteration results from a C to A substitution at nucleotide position 920, causing the proline (P) at amino acid position 307 to be replaced by a glutamine (Q). 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

0.14

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.22

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

T;.;T;.;T;T;T;D

M_CAP

Benign

0.043

MetaRNN

Benign

0.37

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.6

M;M;.;M;M;.;.;.

MutationTaster

Benign

0.95

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.9

D;D;D;D;D;N;D;D

REVEL

Benign

0.18

Sift

Uncertain

0.0070

D;D;D;D;D;T;D;D

Sift4G

Uncertain

0.016

D;D;D;D;D;T;D;T

Polyphen

1.0

D;D;D;D;D;.;.;.

Vest4

0.53

MutPred

0.27

Gain of catalytic residue at S303 (P = 0);Gain of catalytic residue at S303 (P = 0);.;Gain of catalytic residue at S303 (P = 0);Gain of catalytic residue at S303 (P = 0);.;.;.;

MVP

0.44

MPC

0.55

ClinPred

0.78

GERP RS

5.7

Varity_R

0.28

gMVP

0.61

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