11-89178010-T-A

Variant names:

• chr11-89178010-T-A
• rs61753177
• NM_000372.5:c.57T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000372.5(TYR):​c.57T>A​(p.His19Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. H19H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TYR NM_000372.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.0240
• Publications: 3 publications found

Genes affected

TYR (HGNC:12442): (tyrosinase) The enzyme encoded by this gene catalyzes the first 2 steps, and at least 1 subsequent step, in the conversion of tyrosine to melanin. The enzyme has both tyrosine hydroxylase and dopa oxidase catalytic activities, and requires copper for function. Mutations in this gene result in oculocutaneous albinism, and nonpathologic polymorphisms result in skin pigmentation variation. The human genome contains a pseudogene similar to the 3' half of this gene. [provided by RefSeq, Oct 2008]

TYR Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• oculocutaneous albinism type 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Waardenburg syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• minimal pigment oculocutaneous albinism type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• oculocutaneous albinism type 1B

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• temperature-sensitive oculocutaneous albinism type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000372.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 116 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -1.9514 (below the threshold of 3.09). Trascript score misZ: -0.85521 (below the threshold of 3.09). GenCC associations: The gene is linked to Waardenburg syndrome type 2, oculocutaneous albinism type 1A, oculocutaneous albinism type 1, oculocutaneous albinism type 1B, minimal pigment oculocutaneous albinism type 1, temperature-sensitive oculocutaneous albinism type 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5	c.57T>A	p.His19Gln	missense_variant	Exon 1 of 5	ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3	c.57T>A	p.His19Gln	missense_variant	Exon 1 of 6		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6	c.57T>A	p.His19Gln	missense_variant	Exon 1 of 5	1	NM_000372.5	ENSP00000263321.4
TYR	ENST00000526139.1	n.118T>A		non_coding_transcript_exon_variant	Exon 1 of 3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

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Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	0.018
DANN	Benign	0.68
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.019	D
MutationAssessor	Benign	-0.81	N
PhyloP100		0.024
PrimateAI	Benign	0.34	T
PROVEAN	Benign	3.5	N
REVEL	Uncertain	0.52
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.69
MutPred		0.87		Gain of disorder (P = 0.2623);
MVP		0.77
MPC		0.011
ClinPred		0.091	T
GERP RS		-12
PromoterAI		-0.013	Neutral
Varity_R		0.043
gMVP		0.74
Mutation Taster		=28/72	disease causing

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: rs61753177; hg19: chr11-88911178;