Genetic Variant TYR:c.-301C>T (chr11-89177653-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.849

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

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 link	c.-301C>T		upstream_gene_variant		ENST00000263321.6	NP_000363.1	P14679-1L8B082
TYR	XM_011542970.3 link	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 link	c.-301C>T		upstream_gene_variant		1	NM_000372.5	ENSP00000263321.4		P14679-1
TYR	ENST00000526139.1 link	n.-240C>T		upstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.498

AC:

75641

AN:

151916

Hom.:

21383

Cov.:

show subpopulations

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.:

AF XY:

0.375

AC XY:

48285

AN XY:

128644

show subpopulations

Gnomad4 AFR exome

AF:

0.783

Gnomad4 AMR exome

AF:

0.323

Gnomad4 ASJ exome

AF:

0.375

Gnomad4 EAS exome

AF:

0.283

Gnomad4 SAS exome

AF:

0.307

Gnomad4 FIN exome

AF:

0.430

Gnomad4 NFE exome

AF:

0.386

Gnomad4 OTH exome

AF:

0.401

GnomAD4 genome

AF:

0.498

AC:

75760

AN:

152034

Hom.:

21435

Cov.:

AF XY:

0.494

AC XY:

36701

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.790

Gnomad4 AMR

AF:

0.387

Gnomad4 ASJ

AF:

0.388

Gnomad4 EAS

AF:

0.298

Gnomad4 SAS

AF:

0.315

Gnomad4 FIN

AF:

0.432

Gnomad4 NFE

AF:

0.393

Gnomad4 OTH

AF:

0.478

Alfa

AF:

0.438

Hom.:

4821

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

LINK: link

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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over