12-55955822-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001384361.1(PMEL):c.1513G>A(p.Gly505Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00428 in 1,614,050 control chromosomes in the GnomAD database, including 269 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G505D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (146 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (123 hom.)
• Consequence: PMEL NM_001384361.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.10

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014944077).
• BP6: Variant 12-55955822-C-T is Benign according to our data. Variant chr12-55955822-C-T is described in ClinVar as [Benign]. Clinvar id is 789322.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMEL	NM_001384361.1	c.1513G>A	p.Gly505Ser	missense_variant	8/11	ENST00000548747.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMEL	ENST00000548747.6	c.1513G>A	p.Gly505Ser	missense_variant	8/11	1	NM_001384361.1	P4

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3553 AN: 152112 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.0810

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00607 AC: 1526 AN: 251438 Hom.: 66 AF XY: 0.00425 AC XY: 578 AN XY: 135902

Gnomad AFR exome AF: 0.0840

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00229 AC: 3345 AN: 1461820 Hom.: 123 Cov.: 31 AF XY: 0.00189 AC XY: 1371 AN XY: 727220

Gnomad4 AFR exome AF: 0.0819

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.00447

GnomAD4 genome AF: 0.0235 AC: 3570 AN: 152230 Hom.: 146 Cov.: 32 AF XY: 0.0232 AC XY: 1730 AN XY: 74442

Gnomad4 AFR AF: 0.0812

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00429 Hom.: 32

Bravo AF: 0.0268

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0842 AC: 371

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00780 AC: 947

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	10
Dann	Benign	0.68
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.35	T;.;T;.;T;T
MetaRNN	Benign	0.0015	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N;N;.;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.61	N;N;N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.87	T;T;T;T;T;T
Sift4G	Benign	0.64	T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B;.
Vest4		0.16
MVP		0.15
MPC		0.12
ClinPred		0.0026	T
GERP RS		3.0
Varity_R		0.043
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs76045902; hg19: chr12-56349606; COSMIC: COSV99045604; COSMIC: COSV99045604;