dbSNP rs761776915: TYRP1:p.Met452Val (chr9-12708089-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000550.3(TYRP1):c.1354A>G(p.Met452Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,612,750 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

TYRP1
NM_000550.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.95

Publications

2 publications found

Variant links:

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]

TYRP1 links:

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

LURAP1L-AS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000550.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.842

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.1354A>G	p.Met452Val	missense	Exon 7 of 8	NP_000541.1	P17643
	LURAP1L-AS1	NR_125775.1		n.317-7463T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TYRP1	ENST00000388918.10	TSL:1 MANE Select	c.1354A>G	p.Met452Val	missense	Exon 7 of 8	ENSP00000373570.4	P17643
TYRP1	ENST00000381136.2	TSL:2	c.484A>G	p.Met162Val	missense	Exon 4 of 5	ENSP00000370528.2	E7EQI3
TYRP1	ENST00000473504.1	TSL:2	n.419A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000250

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000439

AC:

AN:

250384

AF XY:

0.0000517

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000972

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000171

AC:

250

AN:

1460736

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

122

AN XY:

726682

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33406

American (AMR)

AF:

0.00

AC:

AN:

44572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000207

AC:

230

AN:

1111358

Other (OTH)

AF:

0.000315

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000118

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74236

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

67972

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000259

Hom.:

Bravo

AF:

0.000136

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Oculocutaneous albinism type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.48

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.84

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.0

PhyloP100

8.9

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.4

REVEL

Pathogenic

0.78

Sift

Benign

0.14

Sift4G

Benign

0.17

Varity_R

0.62

gMVP

0.90

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over