rs10830253

Variant names:

• chr11-89294875-T-G
• rs10830253
• NM_000372.5:c.1367-268T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000372.5(TYR):​c.1367-268T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 152,088 control chromosomes in the GnomAD database, including 6,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.28 (6369 hom., cov: 32)
• Consequence: TYR NM_000372.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0350
• Publications: 16 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-89294875-T-G is Benign according to our data. Variant chr11-89294875-T-G is described in ClinVar as Benign. ClinVar VariationId is 1259078.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5	c.1367-268T>G		intron_variant	Intron 4 of 4	ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3	c.*45-268T>G		intron_variant	Intron 5 of 5		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6	c.1367-268T>G		intron_variant	Intron 4 of 4	1	NM_000372.5	ENSP00000263321.4
TYR	ENST00000528243.1	n.365-268T>G		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43301 AN: 151968 Hom.: 6364 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.267

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.285 AC: 43326 AN: 152088 Hom.: 6369 Cov.: 32 AF XY: 0.280 AC XY: 20801 AN XY: 74336

African (AFR) AF: 0.290 AC: 12032 AN: 41466

American (AMR) AF: 0.238 AC: 3645 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 936 AN: 3470

East Asian (EAS) AF: 0.165 AC: 852 AN: 5178

South Asian (SAS) AF: 0.111 AC: 537 AN: 4820

European-Finnish (FIN) AF: 0.309 AC: 3270 AN: 10570

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.312 AC: 21181 AN: 67968

Other (OTH) AF: 0.265 AC: 560 AN: 2116

Alfa AF: 0.290 Hom.: 1111

Bravo AF: 0.281

Asia WGS AF: 0.144 AC: 504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.62
PhyloP100		-0.035
Mutation Taster		=100/0	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: rs10830253; hg19: chr11-89028043; COSMIC: COSV107209066; COSMIC: COSV107209066;