chr11-89284793-G-A

Variant names:

• chr11-89284793-G-A
• rs1126809
• NM_000372.5:c.1205G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 7P and 12B. PS3 PM1 PP2 BP4_Strong BA1

The NM_000372.5(TYR):​c.1205G>A​(p.Arg402Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,610,930 control chromosomes in the GnomAD database, including 56,368 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars). ClinVar reports functional evidence for this variant: "SCV004174896: Functional and phenotypic studies of the complex allele (p.[Arg402Gln" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (3239 hom., cov: 32)
  • Exomes 𝑓: 0.25 (53129 hom.)
• Consequence: TYR NM_000372.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:6 U:9 B:6 O:7
• Conservation: PhyloP100: 7.56
• 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: Orphanet, G2P, 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_benign. The variant received -5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004174896: Functional and phenotypic studies of the complex allele (p.[Arg402Gln;Ser192Tyr]) indicate that the two substitutions have a compound effect on thermal stability of the protein and phenotypic spectrum of the individual (Tripathi et al. 1991. PubMed ID: 1820207; Chaki et al. 2011. PubMed ID: 20861851; Jagirdar et al. 2014. PubMed ID: 24739399).
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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 1B, temperature-sensitive oculocutaneous albinism type 1, oculocutaneous albinism type 1, minimal pigment oculocutaneous albinism type 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029481053).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.276 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYR	NM_000372.5	MANE Select	c.1205G>A	p.Arg402Gln	missense	Exon 4 of 5	NP_000363.1	P14679-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYR	ENST00000263321.6	TSL:1 MANE Select	c.1205G>A	p.Arg402Gln	missense	Exon 4 of 5	ENSP00000263321.4	P14679-1
	TYR	ENST00000528243.1	TSL:5	n.203G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26853 AN: 151504 Hom.: 3237 Cov.: 32

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.00156

Gnomad SAS AF: 0.0612

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.176 AC: 44164 AN: 250300 AF XY: 0.180

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.254 AC: 370235 AN: 1459308 Hom.: 53129 Cov.: 33 AF XY: 0.248 AC XY: 179800 AN XY: 726048

African (AFR) AF: 0.0410 AC: 1367 AN: 33360

American (AMR) AF: 0.106 AC: 4717 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6326 AN: 26044

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39662

South Asian (SAS) AF: 0.0686 AC: 5918 AN: 86208

European-Finnish (FIN) AF: 0.169 AC: 9002 AN: 53360

Middle Eastern (MID) AF: 0.192 AC: 1103 AN: 5744

European-Non Finnish (NFE) AF: 0.295 AC: 327323 AN: 1110140

Other (OTH) AF: 0.240 AC: 14469 AN: 60232

GnomAD4 genome AF: 0.177 AC: 26851 AN: 151622 Hom.: 3239 Cov.: 32 AF XY: 0.168 AC XY: 12473 AN XY: 74092

African (AFR) AF: 0.0499 AC: 2065 AN: 41410

American (AMR) AF: 0.159 AC: 2421 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 826 AN: 3458

East Asian (EAS) AF: 0.00156 AC: 8 AN: 5120

South Asian (SAS) AF: 0.0621 AC: 299 AN: 4816

European-Finnish (FIN) AF: 0.159 AC: 1675 AN: 10552

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18915 AN: 67770

Other (OTH) AF: 0.186 AC: 389 AN: 2096

Alfa AF: 0.243 Hom.: 10766

Bravo AF: 0.172

TwinsUK AF: 0.285 AC: 1058

ALSPAC AF: 0.292 AC: 1124

ESP6500AA AF: 0.0507 AC: 223

ESP6500EA AF: 0.281 AC: 2418

ExAC AF: 0.176 AC: 21389

Asia WGS AF: 0.0310 AC: 111 AN: 3478

EpiCase AF: 0.276

EpiControl AF: 0.273

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; other

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	3	2	Oculocutaneous albinism type 1A (6)
1	2	2	not provided (7)
-	1	1	not specified (2)
2	-	-	Oculocutaneous albinism type 1B (3)
-	1	-	Albinism or congenital nystagmus (1)
1	-	-	Albinism;C0235996:Elevated circulating hepatic transaminase concentration;C0600518:Choroidal neovascularization;C1853141:Slow decrease in visual acuity;C2673946:Foveal hypoplasia;C4021768:Abnormality of metabolism/homeostasis (1)
-	-	1	Malignant tumor of breast (1)
-	1	-	Oculocutaneous albinism type 1 (1)
-	1	-	Pigmentary skin disorders (1)
1	-	-	Temperature-sensitive oculocutaneous albinism type 1 (1)
-	-	-	Autosomal recessive ocular albinism (1)
-	-	-	Melanoma, cutaneous malignant, susceptibility to, 8 (1)
-	-	-	Skin/hair/eye pigmentation 3, blue/green eyes (1)
-	-	-	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.8	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.6
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.029	D
Sift4G	Benign	0.080	T
Polyphen		1.0	D
Vest4		0.16
MPC		0.066
ClinPred		0.017	T
GERP RS		4.7
Varity_R		0.57
gMVP		0.86
Mutation Taster		=78/22	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: rs1126809; hg19: chr11-89017961; COSMIC: COSV54472906;