chr11-89178528-C-A

Variant names:

• chr11-89178528-C-A
• rs1042602
• NM_000372.5:c.575C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP2 BP4_Strong BA1

The NM_000372.5(TYR):​c.575C>A​(p.Ser192Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.314 in 1,613,856 control chromosomes in the GnomAD database, including 90,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.24 (6055 hom., cov: 32)
  • Exomes 𝑓: 0.32 (84395 hom.)
• Consequence: TYR NM_000372.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4 B:9 O:3
• Conservation: PhyloP100: 4.50
• Publications: 211 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: Benign. The variant received -9 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, 5 uncertain in NM_000372.5
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0053822994).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000372.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYR	NM_000372.5	MANE Select	c.575C>A	p.Ser192Tyr	missense	Exon 1 of 5	NP_000363.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYR	ENST00000263321.6	TSL:1 MANE Select	c.575C>A	p.Ser192Tyr	missense	Exon 1 of 5	ENSP00000263321.4
	TYR	ENST00000526139.1	TSL:1	n.636C>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36804 AN: 151964 Hom.: 6055 Cov.: 32

Gnomad AFR AF: 0.0670

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.0979

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.304

GnomAD2 exomes AF: 0.254 AC: 63923 AN: 251456 AF XY: 0.261

Gnomad AFR exome AF: 0.0594

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.450

Gnomad EAS exome AF: 0.000815

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.369

Gnomad OTH exome AF: 0.319

GnomAD4 exome AF: 0.322 AC: 470738 AN: 1461774 Hom.: 84395 Cov.: 40 AF XY: 0.319 AC XY: 231839 AN XY: 727190

African (AFR) AF: 0.0507 AC: 1699 AN: 33478

American (AMR) AF: 0.216 AC: 9646 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 11723 AN: 26136

East Asian (EAS) AF: 0.000932 AC: 37 AN: 39700

South Asian (SAS) AF: 0.114 AC: 9853 AN: 86256

European-Finnish (FIN) AF: 0.181 AC: 9695 AN: 53418

Middle Eastern (MID) AF: 0.323 AC: 1860 AN: 5766

European-Non Finnish (NFE) AF: 0.367 AC: 408104 AN: 1111902

Other (OTH) AF: 0.300 AC: 18121 AN: 60394

GnomAD4 genome AF: 0.242 AC: 36791 AN: 152082 Hom.: 6055 Cov.: 32 AF XY: 0.231 AC XY: 17181 AN XY: 74342

African (AFR) AF: 0.0668 AC: 2772 AN: 41506

American (AMR) AF: 0.271 AC: 4148 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1577 AN: 3468

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5170

South Asian (SAS) AF: 0.0986 AC: 475 AN: 4816

European-Finnish (FIN) AF: 0.183 AC: 1933 AN: 10572

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24808 AN: 67954

Other (OTH) AF: 0.301 AC: 636 AN: 2112

Alfa AF: 0.330 Hom.: 45086

Bravo AF: 0.246

TwinsUK AF: 0.376 AC: 1396

ALSPAC AF: 0.375 AC: 1445

ESP6500AA AF: 0.0756 AC: 333

ESP6500EA AF: 0.377 AC: 3239

ExAC AF: 0.252 AC: 30574

Asia WGS AF: 0.0530 AC: 185 AN: 3478

EpiCase AF: 0.391

EpiControl AF: 0.401

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Oculocutaneous albinism type 1A (6)
1	-	2	not provided (4)
-	1	2	not specified (3)
-	1	1	Oculocutaneous albinism (2)
-	1	-	Albinism or congenital nystagmus (1)
1	-	-	Oculocutaneous albinism type 1B (1)
1	-	-	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.8	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.5
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.35
Sift	Benign	0.031	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.38
MPC		0.069
ClinPred		0.015	T
GERP RS		6.1
Varity_R		0.16
gMVP		0.69
Mutation Taster		=84/16	polymorphism (auto)

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: rs1042602; hg19: chr11-88911696; COSMIC: COSV54472920;