11-89177913-A-G

Variant names:

• chr11-89177913-A-G
• rs886048744
• ENST00000526139.1:n.21A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000372.5(TYR):​c.-41A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000234 in 1,450,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: TYR NM_000372.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.478
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5	c.-41A>G		5_prime_UTR_variant	Exon 1 of 5	ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3	c.-41A>G		5_prime_UTR_variant	Exon 1 of 6		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000526139.1	n.21A>G		non_coding_transcript_exon_variant	Exon 1 of 3	1
TYR	ENST00000263321.6	c.-41A>G		5_prime_UTR_variant	Exon 1 of 5	1	NM_000372.5	ENSP00000263321.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000234 AC: 34 AN: 1450026 Hom.: 0 Cov.: 27 AF XY: 0.0000291 AC XY: 21 AN XY: 722218

African (AFR) AF: 0.00 AC: 0 AN: 33266

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4874

European-Non Finnish (NFE) AF: 0.0000281 AC: 31 AN: 1102810

Other (OTH) AF: 0.0000333 AC: 2 AN: 59984

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oculocutaneous albinism Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.33
DANN	Benign	0.52
PhyloP100		-0.48
PromoterAI		0.017	Neutral

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: rs886048744; hg19: chr11-88911081;