11-89284958-A-G

Variant names:

• chr11-89284958-A-G
• rs61754398
• NM_000372.5:c.1366+4A>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_000372.5(TYR):​c.1366+4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00234 in 1,610,256 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: TYR NM_000372.5 splice_region, intron
• Scores: Splicing: ADA: 0.2757
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1 O:1
• Conservation: PhyloP100: 3.70

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS2: High Homozygotes in GnomAdExome4 at 9 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5	c.1366+4A>G		splice_region_variant, intron_variant	Intron 4 of 4	ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3	c.1366+4A>G		splice_region_variant, intron_variant	Intron 4 of 5		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6	c.1366+4A>G		splice_region_variant, intron_variant	Intron 4 of 4	1	NM_000372.5	ENSP00000263321.4
TYR	ENST00000528243.1	n.364+4A>G		splice_region_variant, intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 247 AN: 151868 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000920

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00292

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00150 AC: 374 AN: 249624 Hom.: 0 AF XY: 0.00141 AC XY: 191 AN XY: 134994

Gnomad AFR exome AF: 0.000374

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000880

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.00241 AC: 3521 AN: 1458270 Hom.: 9 Cov.: 30 AF XY: 0.00235 AC XY: 1706 AN XY: 725590

Gnomad4 AFR exome AF: 0.000270

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00105

Gnomad4 NFE exome AF: 0.00303

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00163 AC: 247 AN: 151986 Hom.: 0 Cov.: 32 AF XY: 0.00159 AC XY: 118 AN XY: 74304

Gnomad4 AFR AF: 0.000482

Gnomad4 AMR AF: 0.000919

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00292

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00218 Hom.: 0

Bravo AF: 0.00135

EpiCase AF: 0.00191

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1 Other:1

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TYR: PM2, BP4 -

not specified Uncertain:1

Jan 13, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1366+4A>G variant in the TYR gene has been reported previously in the heterozygous state in an individual with oculocutaneous albinism type 1B (Hutton et al., 2008). This variant reduces the quality of the splice donor site in intron 4, and is expected to cause abnormal gene splicing. However, the NHLBI Exome Sequencing Project reports that c.1366+4A>G was observed in 23/8592 alleles (0.26%) from individuals of European American ancestry, including one homozygous individual within this control population. Based on the currently available data, we interpret c.1366+4A>G as a variant of uncertain significance. -

Oculocutaneous albinism Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oculocutaneous albinism type 1A Uncertain:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Oculocutaneous albinism type 1A;CN028925:Ocular albinism with congenital sensorineural hearing loss Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	16
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.28
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.11		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: rs61754398; hg19: chr11-89018126;