chr9-12694274-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000550.3(TYRP1):c.278G>A(p.Arg93His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00745 in 1,613,804 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0065 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0075 ( 66 hom. )

Consequence

TYRP1
NM_000550.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.24

Publications

13 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

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009429097).

BP6

Variant 9-12694274-G-A is Benign according to our data. Variant chr9-12694274-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195092.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00651 (991/152236) while in subpopulation NFE AF = 0.0104 (706/68026). AF 95% confidence interval is 0.00974. There are 11 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 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.278G>A	p.Arg93His	missense	Exon 2 of 8	NP_000541.1	P17643

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TYRP1	ENST00000388918.10	TSL:1 MANE Select	c.278G>A	p.Arg93His	missense	Exon 2 of 8	ENSP00000373570.4	P17643
TYRP1	ENST00000473763.1	TSL:4	c.278G>A	p.Arg93His	missense	Exon 2 of 2	ENSP00000419006.1	C9JZ52
TYRP1	ENST00000459790.1	TSL:2	n.533G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00651

AC:

991

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00641

AC:

1602

AN:

249796

AF XY:

0.00654

show subpopulations

Gnomad AFR exome

AF:

0.00118

Gnomad AMR exome

AF:

0.00218

Gnomad ASJ exome

AF:

0.00389

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0122

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.00688

GnomAD4 exome

AF:

0.00754

AC:

11026

AN:

1461568

Hom.:

Cov.:

AF XY:

0.00748

AC XY:

5435

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

33476

American (AMR)

AF:

0.00248

AC:

111

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00367

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39662

South Asian (SAS)

AF:

0.000557

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.0111

AC:

591

AN:

53388

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00879

AC:

9770

AN:

1111892

Other (OTH)

AF:

0.00601

AC:

363

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

707

1414

2122

2829

3536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

318

636

954

1272

1590

<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:

0.00651

AC:

991

AN:

152236

Hom.:

Cov.:

AF XY:

0.00661

AC XY:

492

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

41526

American (AMR)

AF:

0.00536

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0117

AC:

124

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0104

AC:

706

AN:

68026

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00820

Hom.:

Bravo

AF:

0.00479

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00687

AC:

834

EpiCase

AF:

0.00752

EpiControl

AF:

0.00789

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Oculocutaneous albinism type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.0094

MetaSVM

Uncertain

0.0094

MutationAssessor

Uncertain

2.5

PhyloP100

2.2

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.30

Sift

Uncertain

0.013

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.72

MVP

0.92

MPC

0.019

ClinPred

0.035

GERP RS

2.7

Varity_R

0.51

gMVP

0.82

Mutation Taster

=70/30

polymorphism

(source)

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

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