12-55955270-T-TTACCTATATATATATATA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001384361.1(PMEL):c.1850+3_1850+4insTATATATATATATAGGTA variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,600,952 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (3 hom.)
• Consequence: PMEL NM_001384361.1 splice_donor_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.160

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 -10 ACMG points.

• BP6: Variant 12-55955270-T-TTACCTATATATATATATA is Benign according to our data. Variant chr12-55955270-T-TTACCTATATATATATATA is described in ClinVar as [Benign]. Clinvar id is 781077.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00579 (882/152258) while in subpopulation AFR AF= 0.0205 (853/41522). AF 95% confidence interval is 0.0194. There are 8 homozygotes in gnomad4. There are 425 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMEL	NM_001384361.1	c.1850+3_1850+4insTATATATATATATAGGTA		splice_donor_region_variant, intron_variant		ENST00000548747.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMEL	ENST00000548747.6	c.1850+3_1850+4insTATATATATATATAGGTA		splice_donor_region_variant, intron_variant		1	NM_001384361.1	P4

Frequencies

GnomAD3 genomes AF: 0.00580 AC: 882 AN: 152140 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

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: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000760 AC: 191 AN: 251200 Hom.: 0 AF XY: 0.000589 AC XY: 80 AN XY: 135814

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.000289

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: 0.000544 AC: 788 AN: 1448694 Hom.: 3 Cov.: 28 AF XY: 0.000462 AC XY: 333 AN XY: 721516

Gnomad4 AFR exome AF: 0.0213

Gnomad4 AMR exome AF: 0.000582

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: 0.00000364

Gnomad4 OTH exome AF: 0.000900

GnomAD4 genome AF: 0.00579 AC: 882 AN: 152258 Hom.: 8 Cov.: 32 AF XY: 0.00571 AC XY: 425 AN XY: 74458

Gnomad4 AFR AF: 0.0205

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00296 Hom.: 1

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

May 21, 2018

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs370539038; hg19: chr12-56349054;