chr11-89177755-C-A

Variant names:

• chr11-89177755-C-A
• rs1799989
• NM_000372.5:c.-199C>A

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.-199C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 614,940 control chromosomes in the GnomAD database, including 6,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2448 hom., cov: 32)
  • Exomes 𝑓: 0.13 (4410 hom.)
• Consequence: TYR NM_000372.5 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.278
• Publications: 11 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=-0.82).
• BP6: Variant 11-89177755-C-A is Benign according to our data. Variant chr11-89177755-C-A is described in ClinVar as Benign. ClinVar VariationId is 3783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5	c.-199C>A		upstream_gene_variant		ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3	c.-199C>A		upstream_gene_variant			XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6	c.-199C>A		upstream_gene_variant		1	NM_000372.5	ENSP00000263321.4
TYR	ENST00000526139.1	n.-138C>A		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24948 AN: 151944 Hom.: 2430 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.171

GnomAD4 exome AF: 0.130 AC: 59995 AN: 462876 Hom.: 4410 Cov.: 5 AF XY: 0.134 AC XY: 32686 AN XY: 244832

African (AFR) AF: 0.273 AC: 3483 AN: 12772

American (AMR) AF: 0.132 AC: 2776 AN: 20972

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 1636 AN: 14082

East Asian (EAS) AF: 0.141 AC: 4326 AN: 30760

South Asian (SAS) AF: 0.205 AC: 9581 AN: 46848

European-Finnish (FIN) AF: 0.164 AC: 4886 AN: 29800

Middle Eastern (MID) AF: 0.183 AC: 360 AN: 1966

European-Non Finnish (NFE) AF: 0.105 AC: 29413 AN: 279462

Other (OTH) AF: 0.135 AC: 3534 AN: 26214

GnomAD4 genome AF: 0.164 AC: 25008 AN: 152064 Hom.: 2448 Cov.: 32 AF XY: 0.167 AC XY: 12415 AN XY: 74342

African (AFR) AF: 0.275 AC: 11389 AN: 41474

American (AMR) AF: 0.140 AC: 2137 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 409 AN: 3472

East Asian (EAS) AF: 0.119 AC: 615 AN: 5168

South Asian (SAS) AF: 0.201 AC: 964 AN: 4806

European-Finnish (FIN) AF: 0.174 AC: 1839 AN: 10570

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7169 AN: 67964

Other (OTH) AF: 0.176 AC: 372 AN: 2110

Alfa AF: 0.154 Hom.: 611

Bravo AF: 0.166

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

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

- -

Oculocutaneous albinism type 1A Benign:1

Jan 01, 1993

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.62
PhyloP100		-0.28
PromoterAI		0.022	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: rs1799989; hg19: chr11-88910923;