rs773970123

Variant names:

• chr11-89227823-G-A
• rs773970123
• NM_000372.5:c.1037G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-89227823-G-A
• chr11-89227823-G-C
• chr11-89227823-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM5 PP2 PP3 PP5_Very_Strong

The NM_000372.5(TYR):​c.1037G>A​(p.Gly346Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,460,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G346R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TYR NM_000372.5 missense, splice_region
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.36
• Publications: 8 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000372.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-89191418-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1477155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 116 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -1.9514 (below the threshold of 3.09). Trascript score misZ: -0.85521 (below the threshold of 3.09). GenCC associations: The gene is linked to Waardenburg syndrome type 2, oculocutaneous albinism type 1A, oculocutaneous albinism type 1, oculocutaneous albinism type 1B, minimal pigment oculocutaneous albinism type 1, temperature-sensitive oculocutaneous albinism type 1.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 11-89227823-G-A is Pathogenic according to our data. Variant chr11-89227823-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 617799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000372.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYR	NM_000372.5	MANE Select	c.1037G>A	p.Gly346Glu	missense splice_region	Exon 3 of 5	NP_000363.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYR	ENST00000263321.6	TSL:1 MANE Select	c.1037G>A	p.Gly346Glu	missense splice_region	Exon 3 of 5	ENSP00000263321.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250116 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460186 Hom.: 0 Cov.: 32 AF XY: 0.00000964 AC XY: 7 AN XY: 726482

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111420

Other (OTH) AF: 0.0000166 AC: 1 AN: 60348

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000299 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Oculocutaneous albinism type 1 (2)
1	-	-	Abnormality of the skin (1)
1	-	-	Nonsyndromic Oculocutaneous Albinism (1)
1	-	-	not provided (1)
1	-	-	Oculocutaneous albinism (1)
1	-	-	Oculocutaneous albinism type 1B;C4551504:Oculocutaneous albinism type 1A (1)
1	-	-	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.82		Gain of disorder (P = 0.0751)
MVP		1.0
MPC		0.074
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.95
gMVP		0.96
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
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

Other links and lift over

dbSNP: rs773970123; hg19: chr11-88960991;