9-12702424-G-T

Position:

• chr9-12702424-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000550.3(TYRP1):​c.1067G>T​(p.Arg356Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R356Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TYRP1 NM_000550.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-12702424-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYRP1	NM_000550.3	c.1067G>T	p.Arg356Leu	missense_variant	5/8	ENST00000388918.10	NP_000541.1
LURAP1L-AS1	NR_125775.1	n.317-1798C>A		intron_variant, non_coding_transcript_variant
TYRP1	XM_047423841.1	c.862G>T	p.Glu288Ter	stop_gained	4/5		XP_047279797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYRP1	ENST00000388918.10	c.1067G>T	p.Arg356Leu	missense_variant	5/8	1	NM_000550.3	ENSP00000373570	P1
LURAP1L-AS1	ENST00000417638.1	n.273-1798C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460568 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726600

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.67		Loss of catalytic residue at R356 (P = 0.0024);.;
MVP		1.0
MPC		0.027
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs281865424; hg19: chr9-12702424;