rs3793975

Positions:

• chr11-89228020-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000372.5(TYR):​c.1184+50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,596,530 control chromosomes in the GnomAD database, including 14,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2607 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12048 hom.)
• Consequence: TYR NM_000372.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.107

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-89228020-G-A is Benign according to our data. Variant chr11-89228020-G-A is described in ClinVar as [Benign]. Clinvar id is 1281825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYR	NM_000372.5	c.1184+50G>A		intron_variant		ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3	c.1184+50G>A		intron_variant			XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6	c.1184+50G>A		intron_variant		1	NM_000372.5	ENSP00000263321.4

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25355 AN: 151862 Hom.: 2587 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.177

GnomAD3 exomes AF: 0.140 AC: 34747 AN: 248150 Hom.: 2897 AF XY: 0.140 AC XY: 18844 AN XY: 134410

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.211

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.122 AC: 176056 AN: 1444552 Hom.: 12048 Cov.: 27 AF XY: 0.124 AC XY: 89574 AN XY: 719698

Gnomad4 AFR exome AF: 0.297

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.149

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.167 AC: 25421 AN: 151978 Hom.: 2607 Cov.: 32 AF XY: 0.168 AC XY: 12483 AN XY: 74234

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.142

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.202

Gnomad4 FIN AF: 0.139

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.182

Alfa AF: 0.134 Hom.: 1004

Bravo AF: 0.172

Asia WGS AF: 0.191 AC: 663 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.23
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs3793975; hg19: chr11-88961188; COSMIC: COSV54477229;