rs387906560

Variant names:

• chr9-12704544-GA-G
• rs387906560
• NM_000550.3:c.1103delA

Your query was ambiguous. Multiple possible variants found:

• chr9-12704544-GA-G
• chr9-12704544-GA-GAA

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_000550.3(TYRP1):​c.1103delA​(p.Lys368SerfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,612,526 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001818747: In vitro studies in cultured fibroblasts from an affected individual homozygous for the c.1103delA variant showed absent TYRP1 mRNA and protein (Boissy et al., 1996);". Synonymous variant affecting the same amino acid position (i.e. K368K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TYRP1 NM_000550.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.340
• Publications: 2 publications found

Genes affected

TYRP1 (HGNC:12450): (tyrosinase related protein 1) This gene encodes a melanosomal enzyme that belongs to the tyrosinase family and plays an important role in the melanin biosynthetic pathway. Defects in this gene are the cause of rufous oculocutaneous albinism and oculocutaneous albinism type III. [provided by RefSeq, Mar 2009]

LURAP1L-AS1 (HGNC:49761): (LURAP1L antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001818747: In vitro studies in cultured fibroblasts from an affected individual homozygous for the c.1103delA variant showed absent TYRP1 mRNA and protein (Boissy et al., 1996)
• PP5: Variant 9-12704544-GA-G is Pathogenic according to our data. Variant chr9-12704544-GA-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000550.3. 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
	TYRP1	NM_000550.3	MANE Select	c.1103delA	p.Lys368SerfsTer17	frameshift	Exon 6 of 8	NP_000541.1	P17643
	LURAP1L-AS1	NR_125775.1		n.317-3919delT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYRP1	ENST00000388918.10	TSL:1 MANE Select	c.1103delA	p.Lys368SerfsTer17	frameshift	Exon 6 of 8	ENSP00000373570.4	P17643
	TYRP1	ENST00000381136.2	TSL:2	c.233delA	p.Lys78SerfsTer17	frameshift	Exon 3 of 5	ENSP00000370528.2	E7EQI3
	TYRP1	ENST00000381142.3	TSL:2	n.340delA		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 151998 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00502

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

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: 0.00143

GnomAD2 exomes AF: 0.000355 AC: 89 AN: 250536 AF XY: 0.000251

Gnomad AFR exome AF: 0.00506

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000106 AC: 155 AN: 1460410 Hom.: 0 Cov.: 32 AF XY: 0.0000785 AC XY: 57 AN XY: 726524

African (AFR) AF: 0.00407 AC: 136 AN: 33408

American (AMR) AF: 0.000202 AC: 9 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111428

Other (OTH) AF: 0.000149 AC: 9 AN: 60296

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152116 Hom.: 1 Cov.: 31 AF XY: 0.00151 AC XY: 112 AN XY: 74364

African (AFR) AF: 0.00503 AC: 209 AN: 41540

American (AMR) AF: 0.000394 AC: 6 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67970

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000192 Hom.: 0

Bravo AF: 0.00161

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
2	-	-	Oculocutaneous albinism type 3 (2)
1	-	-	Albinism (1)
1	-	-	Oculocutaneous albinism type 3;C2677086:MELANESIAN BLOND HAIR (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34
Mutation Taster		=0/200	disease causing (ClinVar)

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

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

Other links and lift over

dbSNP: rs387906560;

hg19: chr9-12704544;