11-89177653-C-T

Variant names:

• chr11-89177653-C-T
• rs4547091
• NM_000372.5:c.-301C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000372.5(TYR):​c.-301C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 394,494 control chromosomes in the GnomAD database, including 40,303 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (21435 hom., cov: 32)
  • Exomes 𝑓: 0.38 (18868 hom.)
• Consequence: TYR NM_000372.5 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.849
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 11-89177653-C-T is Benign according to our data. Variant chr11-89177653-C-T is described in ClinVar as Benign. ClinVar VariationId is 1293219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5	c.-301C>T		upstream_gene_variant		ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3	c.-301C>T		upstream_gene_variant			XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6	c.-301C>T		upstream_gene_variant		1	NM_000372.5	ENSP00000263321.4
TYR	ENST00000526139.1	n.-240C>T		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75641 AN: 151916 Hom.: 21383 Cov.: 32

Gnomad AFR AF: 0.790

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.476

GnomAD4 exome AF: 0.382 AC: 92502 AN: 242460 Hom.: 18868 Cov.: 0 AF XY: 0.375 AC XY: 48285 AN XY: 128644

African (AFR) AF: 0.783 AC: 5960 AN: 7608

American (AMR) AF: 0.323 AC: 3313 AN: 10264

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 2644 AN: 7060

East Asian (EAS) AF: 0.283 AC: 3780 AN: 13352

South Asian (SAS) AF: 0.307 AC: 10629 AN: 34674

European-Finnish (FIN) AF: 0.430 AC: 5012 AN: 11664

Middle Eastern (MID) AF: 0.413 AC: 410 AN: 992

European-Non Finnish (NFE) AF: 0.386 AC: 55356 AN: 143388

Other (OTH) AF: 0.401 AC: 5398 AN: 13458

GnomAD4 genome AF: 0.498 AC: 75760 AN: 152034 Hom.: 21435 Cov.: 32 AF XY: 0.494 AC XY: 36701 AN XY: 74296

African (AFR) AF: 0.790 AC: 32788 AN: 41498

American (AMR) AF: 0.387 AC: 5906 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1346 AN: 3468

East Asian (EAS) AF: 0.298 AC: 1534 AN: 5148

South Asian (SAS) AF: 0.315 AC: 1515 AN: 4814

European-Finnish (FIN) AF: 0.432 AC: 4557 AN: 10552

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26735 AN: 67968

Other (OTH) AF: 0.478 AC: 1009 AN: 2112

Alfa AF: 0.439 Hom.: 6016

Bravo AF: 0.507

Asia WGS AF: 0.353 AC: 1226 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22259223) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.44
DANN	Benign	0.51
PhyloP100		-0.85
PromoterAI		0.014	Neutral
Mutation Taster		=300/0	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: rs4547091; hg19: chr11-88910821;