12-55955511-G-A

Variant names:

• chr12-55955511-G-A
• NM_001384361.1:c.1715C>T
• PMEL p.Ala572Val

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001384361.1(PMEL):​c.1715C>T​(p.Ala572Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PMEL NM_001384361.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.39
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384361.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMEL	NM_001384361.1	MANE Select	c.1715C>T	p.Ala572Val	missense	Exon 9 of 11	NP_001371290.1	P40967-1
	PMEL	NM_001200054.1		c.1715C>T	p.Ala572Val	missense	Exon 9 of 11	NP_001186983.1	P40967-2
	PMEL	NM_006928.5		c.1715C>T	p.Ala572Val	missense	Exon 10 of 12	NP_008859.1	P40967-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMEL	ENST00000548747.6	TSL:1 MANE Select	c.1715C>T	p.Ala572Val	missense	Exon 9 of 11	ENSP00000448828.1	P40967-1
	PMEL	ENST00000449260.6	TSL:1	c.1715C>T	p.Ala572Val	missense	Exon 9 of 11	ENSP00000402758.2	P40967-2
	PMEL	ENST00000548493.5	TSL:2	c.1715C>T	p.Ala572Val	missense	Exon 10 of 12	ENSP00000447374.1	P40967-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.4
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.019	D
Varity_R		0.15
gMVP		0.67
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-56349295;