rs28521275

Variant names:

• chr11-89295801-C-T
• rs28521275
• NM_000372.5:c.*435C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000372.5(TYR):​c.*435C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 184,664 control chromosomes in the GnomAD database, including 29,478 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (27049 hom., cov: 32)
  • Exomes 𝑓: 0.38 (2429 hom.)
• Consequence: TYR NM_000372.5 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.207
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.812 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.*435C>T		downstream_gene	N/A	NP_000363.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYR	ENST00000263321.6	TSL:1 MANE Select	c.*435C>T		downstream_gene	N/A	ENSP00000263321.4

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87479 AN: 151828 Hom.: 26996 Cov.: 32

Gnomad AFR AF: 0.819

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.524

GnomAD4 exome AF: 0.377 AC: 12343 AN: 32718 Hom.: 2429 Cov.: 0 AF XY: 0.376 AC XY: 6497 AN XY: 17286

African (AFR) AF: 0.684 AC: 119 AN: 174

American (AMR) AF: 0.451 AC: 1411 AN: 3132

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 159 AN: 572

East Asian (EAS) AF: 0.406 AC: 790 AN: 1946

South Asian (SAS) AF: 0.345 AC: 1716 AN: 4980

European-Finnish (FIN) AF: 0.395 AC: 401 AN: 1016

Middle Eastern (MID) AF: 0.328 AC: 21 AN: 64

European-Non Finnish (NFE) AF: 0.369 AC: 7108 AN: 19260

Other (OTH) AF: 0.393 AC: 618 AN: 1574

GnomAD4 genome AF: 0.577 AC: 87603 AN: 151946 Hom.: 27049 Cov.: 32 AF XY: 0.576 AC XY: 42814 AN XY: 74274

African (AFR) AF: 0.820 AC: 33988 AN: 41460

American (AMR) AF: 0.524 AC: 7998 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1390 AN: 3470

East Asian (EAS) AF: 0.491 AC: 2525 AN: 5140

South Asian (SAS) AF: 0.454 AC: 2187 AN: 4814

European-Finnish (FIN) AF: 0.563 AC: 5934 AN: 10548

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.468 AC: 31816 AN: 67928

Other (OTH) AF: 0.527 AC: 1113 AN: 2110

Alfa AF: 0.543 Hom.: 2914

Bravo AF: 0.581

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.0
DANN	Benign	0.45
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs28521275; hg19: chr11-89028969;