12-55957193-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384361.1(PMEL):c.1110G>C(p.Glu370Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,614,200 control chromosomes in the GnomAD database, including 245 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (116 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (129 hom.)
• Consequence: PMEL NM_001384361.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.460

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022105873).
• BP6: Variant 12-55957193-C-G is Benign according to our data. Variant chr12-55957193-C-G is described in ClinVar as [Benign]. Clinvar id is 769389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMEL	NM_001384361.1	c.1110G>C	p.Glu370Asp	missense_variant	6/11	ENST00000548747.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMEL	ENST00000548747.6	c.1110G>C	p.Glu370Asp	missense_variant	6/11	1	NM_001384361.1	P4

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3569 AN: 152210 Hom.: 116 Cov.: 32

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.00789 AC: 1984 AN: 251480 Hom.: 58 AF XY: 0.00669 AC XY: 909 AN XY: 135920

Gnomad AFR exome AF: 0.0764

Gnomad AMR exome AF: 0.00867

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00255

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.00412 AC: 6016 AN: 1461872 Hom.: 129 Cov.: 32 AF XY: 0.00387 AC XY: 2811 AN XY: 727242

Gnomad4 AFR exome AF: 0.0773

Gnomad4 AMR exome AF: 0.00926

Gnomad4 ASJ exome AF: 0.00440

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00150

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00198

Gnomad4 OTH exome AF: 0.00780

GnomAD4 genome AF: 0.0235 AC: 3577 AN: 152328 Hom.: 116 Cov.: 32 AF XY: 0.0227 AC XY: 1694 AN XY: 74488

Gnomad4 AFR AF: 0.0734

Gnomad4 AMR AF: 0.0192

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00587 Hom.: 12

Bravo AF: 0.0276

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0738 AC: 325

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00875 AC: 1062

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00362

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2019	This variant is associated with the following publications: (PMID: 30561643) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	5.5
Dann	Benign	0.86
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.72	T;.;T;.;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M;M;.;M;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.090	N;N;N;N;N;N;N
REVEL	Benign	0.018
Sift	Benign	0.33	T;T;T;T;T;T;D
Sift4G	Benign	0.45	T;T;T;T;T;T;T
Polyphen		0.66	P;P;P;P;P;.;.
Vest4		0.15
MutPred		0.14		Gain of catalytic residue at M366 (P = 0.0042);Gain of catalytic residue at M366 (P = 0.0042);.;Gain of catalytic residue at M366 (P = 0.0042);Gain of catalytic residue at M366 (P = 0.0042);.;.;
MVP		0.23
MPC		0.23
ClinPred		0.0046	T
GERP RS		2.1
Varity_R		0.047
gMVP		0.34

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

Other links and lift over

dbSNP: rs17118154; hg19: chr12-56350977;