9-12709125-T-G

Variant names:

• chr9-12709125-T-G
• rs41302073
• NM_000550.3:c.1557T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000550.3(TYRP1):​c.1557T>G​(p.Tyr519*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,612,736 control chromosomes in the GnomAD database, including 74 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (38 hom.)
• Consequence: TYRP1 NM_000550.3 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.45
• Publications: 10 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-12709125-T-G is Benign according to our data. Variant chr9-12709125-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1588/151986) while in subpopulation AFR AF = 0.0371 (1540/41492). AF 95% confidence interval is 0.0356. There are 36 homozygotes in GnomAd4. There are 731 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

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.1557T>G	p.Tyr519*	stop_gained	Exon 8 of 8	NP_000541.1	P17643
	LURAP1L-AS1	NR_125775.1		n.317-8499A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYRP1	ENST00000388918.10	TSL:1 MANE Select	c.1557T>G	p.Tyr519*	stop_gained	Exon 8 of 8	ENSP00000373570.4	P17643
	TYRP1	ENST00000381136.2	TSL:2	c.687T>G	p.Tyr229*	stop_gained	Exon 5 of 5	ENSP00000370528.2	E7EQI3
	TYRP1	ENST00000381142.3	TSL:2	n.647T>G		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1589 AN: 151868 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00217

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: 0.0000442

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00267 AC: 670 AN: 250710 AF XY: 0.00184

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.00107 AC: 1569 AN: 1460750 Hom.: 38 Cov.: 33 AF XY: 0.000892 AC XY: 648 AN XY: 726688

African (AFR) AF: 0.0422 AC: 1411 AN: 33422

American (AMR) AF: 0.000896 AC: 40 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111240

Other (OTH) AF: 0.00164 AC: 99 AN: 60314

GnomAD4 genome AF: 0.0104 AC: 1588 AN: 151986 Hom.: 36 Cov.: 32 AF XY: 0.00984 AC XY: 731 AN XY: 74280

African (AFR) AF: 0.0371 AC: 1540 AN: 41492

American (AMR) AF: 0.00217 AC: 33 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67904

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00400 Hom.: 24

Bravo AF: 0.0122

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0409 AC: 180

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00358 AC: 435

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		3.4
Vest4		0.87
GERP RS		2.6
Mutation Taster		=23/177	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41302073; hg19: chr9-12709125;