9-12694042-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000550.3(TYRP1):c.46T>A(p.Leu16Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L16F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TYRP1 NM_000550.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0660

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2119298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYRP1	NM_000550.3	c.46T>A	p.Leu16Met	missense_variant	2/8	ENST00000388918.10
TYRP1	XM_047423841.1	c.46T>A	p.Leu16Met	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYRP1	ENST00000388918.10	c.46T>A	p.Leu16Met	missense_variant	2/8	1	NM_000550.3	P1
TYRP1	ENST00000473763.1	c.46T>A	p.Leu16Met	missense_variant	2/2	4
TYRP1	ENST00000459790.1	n.301T>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 19, 2022

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 16 of the TYRP1 protein (p.Leu16Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TYRP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	1.1
Dann	Benign	0.94
DEOGEN2	Benign	0.077	T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.33	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.64	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.080	T;T
Sift4G	Benign	0.064	T;T
Polyphen		0.68	.;P
Vest4		0.26
MutPred		0.37		Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);
MVP		0.98
MPC		0.0084
ClinPred		0.17	T
GERP RS		1.7
Varity_R		0.073
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs1005251566; hg19: chr9-12694042;