rs61754388

Variant names:

• chr11-89227904-C-A
• rs61754388
• NM_000372.5:c.1118C>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM5 PP2 PP5_Very_Strong

The NM_000372.5(TYR):​c.1118C>A​(p.Thr373Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000882 in 1,613,434 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003839048: Experimental studies in transfected HeLa cells demonstrate that the p.Thr373Lys variant abolishes catalytic activity." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T373A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (1 hom.)
• Consequence: TYR NM_000372.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:27 O:1
• Conservation: PhyloP100: 5.70
• Publications: 31 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: Orphanet, G2P, 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003839048: Experimental studies in transfected HeLa cells demonstrate that the p.Thr373Lys variant abolishes catalytic activity.; SCV000329959: Published functional studies demonstrate a damaging effect, specifically, T373K transfected cells had no tyrosine hydroxylase activity, undetectable melanin production, and showed the T373K mutant protein was unable to leave the endoplasmic reticulum (Tripathi et al., 1992; Toyofuku et al., 2001). A separate in vitro study also suggests improper folding of the T373K protein (Dolinska et al., 2017).; SCV001248574: PS3:Supporting; SCV001580868: Experimental studies have shown that this missense change affects TYR function (PMID: 1429711, 9242509, 27775880).; SCV000245677: "In vitro functional studies suggest this variant leads to abolished TYR activity" (Tripathi 1992).; SCV000374874: Transient expression studies in transfected HeLa cells demonstrated that the p.Thr373Lys variant abolished all three catalytic activities associated with the wild type tyrosinase and was unable to produce melanin (Tripathi et al. 1992).; SCV003839049: Experimental studies in transfected HeLa cells demonstrate that the p.Thr373Lys variant abolishes catalytic activity.; SCV005397661: Functional studies have demonstrated that the protein resulting from this variant has nearly no tyrosinase activity, produces nearly no melanin, fails to leave the endoplasmic reticulum, and is degraded (PMID: 11284711, 1429711, 9242509, 27775880).; SCV005688756: "A functional study indicates that the variant protein shows no enzymatic activity." PMID:27775880
• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000372.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-89227903-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4077112.Status of the report is criteria_provided_single_submitter, 1 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 1B, temperature-sensitive oculocutaneous albinism type 1, oculocutaneous albinism type 1, minimal pigment oculocutaneous albinism type 1.
• PP5: Variant 11-89227904-C-A is Pathogenic according to our data. Variant chr11-89227904-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3774.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYR	NM_000372.5	MANE Select	c.1118C>A	p.Thr373Lys	missense	Exon 3 of 5	NP_000363.1	P14679-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYR	ENST00000263321.6	TSL:1 MANE Select	c.1118C>A	p.Thr373Lys	missense	Exon 3 of 5	ENSP00000263321.4	P14679-1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000343 AC: 86 AN: 250994 AF XY: 0.000413

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000687

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000922 AC: 1348 AN: 1461420 Hom.: 1 Cov.: 32 AF XY: 0.000873 AC XY: 635 AN XY: 727014

African (AFR) AF: 0.0000897 AC: 3 AN: 33460

American (AMR) AF: 0.000112 AC: 5 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00112 AC: 1246 AN: 1111728

Other (OTH) AF: 0.00156 AC: 94 AN: 60380

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152014 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74248

African (AFR) AF: 0.000169 AC: 7 AN: 41392

American (AMR) AF: 0.000131 AC: 2 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000971 AC: 66 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000749 Hom.: 0

Bravo AF: 0.000468

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000819

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (8)
7	-	-	Oculocutaneous albinism type 1A (7)
4	-	-	Oculocutaneous albinism (4)
2	-	-	Oculocutaneous albinism type 1B (2)
2	-	-	Oculocutaneous albinism type 1B;C4551504:Oculocutaneous albinism type 1A (2)
2	-	-	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN (2)
2	-	-	TYR-related disorder (2)
1	-	-	Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Oculocutaneous albinism type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.96	D
Eigen	Benign	0.049
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.0010	B
Vest4		0.77
MVP		1.0
MPC		0.011
ClinPred		0.27	T
GERP RS		4.5
Varity_R		0.90
gMVP		0.87
Mutation Taster		=58/42	disease causing (ClinVar)

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: rs61754388; hg19: chr11-88961072;