rs104894313

Variant names:

• chr11-89284805-C-T
• rs104894313
• NM_000372.5:c.1217C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PS3 PM1 PM5 PP2 PP3 PP5 BP4

The NM_000372.5(TYR):​c.1217C>T​(p.Pro406Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,611,690 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001549874: Functional studies demonstrated that the p.P406L variant destabilizes tyrosinase structure and results in reduced protein activity compared to wildtype (Giebel_1991_PMID_1903591" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P406A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (18 hom.)
• Consequence: TYR NM_000372.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:32 U:3 O:1
• Conservation: PhyloP100: 7.42
• Publications: 34 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 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001549874: Functional studies demonstrated that the p.P406L variant destabilizes tyrosinase structure and results in reduced protein activity compared to wildtype (Giebel_1991_PMID_1903591; Dolinksa_2017_PMID_27775880; Toyofuku_2001_PMID_11284711; Spritz_1997_PMID_9242509).; SCV001583161: Experimental studies have shown that this missense change affects TYR function (PMID: 1429711, 9242509, 11284711).; SCV002499801: Published functional studies suggest a damaging effect with temperature-sensitive tyrosine hydroxylase activity and abnormal subcellular trafficking compared to wild type (PMID: 1429711, 9242509, 11284711, 27775880); SCV000374875: Giebel et al. (1991) demonstrated that the tyrosinase activity in HeLa cells transfected with the p.Pro406Leu variant had only 7% of the activity of wild type. Toyofuku et al. (2001) expressed the p.Pro406Leu variant in COS7 cells and demonstrated that the variant protein is mislocalized, is more sensitive to endoglycosidase H digestion, and degrades more rapidly than wild type protein.; SCV000712802: "In vitro functional studies provide evidence that the p.Pro406Leu variant may impact protein function (Tripathi 1992, Spritz 1997, and Toyofuku 2001)."; SCV003844690: At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant results in less catalytic activity than the wild-type.; SCV001142424: "In vitro function al studies provide evidence that the p.Pro406Leu variant may impact protein func tion (PMID: 1642278; 9242509; 11284711)."; SCV004730906: Functional studies using protein expression in cell culture have shown that the p.Pro406Leu variant results in reduced tyrosinase activity compared to wild-type (Giebel et al. 1991. PubMed ID: 1903591; Dolinska et al. 2017. PubMed ID: 27775880).
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000372.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-89284804-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1947187.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.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• PP5: Variant 11-89284805-C-T is Pathogenic according to our data. Variant chr11-89284805-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3777.
• BP4: Computational evidence support a benign effect (MetaRNN=0.037014306). . Strength limited to SUPPORTING due to the PP5.

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.1217C>T	p.Pro406Leu	missense	Exon 4 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.1217C>T	p.Pro406Leu	missense	Exon 4 of 5	ENSP00000263321.4	P14679-1
	TYR	ENST00000528243.1	TSL:5	n.215C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 563 AN: 151820 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00270

Gnomad ASJ AF: 0.00925

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00448

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00383 AC: 960 AN: 250392 AF XY: 0.00395

Gnomad AFR exome AF: 0.000865

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00855

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.00525

GnomAD4 exome AF: 0.00463 AC: 6761 AN: 1459752 Hom.: 18 Cov.: 32 AF XY: 0.00453 AC XY: 3293 AN XY: 726248

African (AFR) AF: 0.000480 AC: 16 AN: 33366

American (AMR) AF: 0.00184 AC: 82 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00906 AC: 236 AN: 26048

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39662

South Asian (SAS) AF: 0.00198 AC: 171 AN: 86214

European-Finnish (FIN) AF: 0.0107 AC: 570 AN: 53364

Middle Eastern (MID) AF: 0.00557 AC: 32 AN: 5746

European-Non Finnish (NFE) AF: 0.00484 AC: 5377 AN: 1110530

Other (OTH) AF: 0.00456 AC: 275 AN: 60252

GnomAD4 genome AF: 0.00370 AC: 562 AN: 151938 Hom.: 5 Cov.: 32 AF XY: 0.00411 AC XY: 305 AN XY: 74288

African (AFR) AF: 0.00111 AC: 46 AN: 41508

American (AMR) AF: 0.00269 AC: 41 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00925 AC: 32 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4830

European-Finnish (FIN) AF: 0.0108 AC: 115 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00447 AC: 303 AN: 67854

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.00219 Hom.: 1

Bravo AF: 0.00276

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00349 AC: 424

EpiCase AF: 0.00464

EpiControl AF: 0.00522

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
10	-	-	Oculocutaneous albinism type 1A (10)
6	-	-	not provided (7)
4	1	-	Oculocutaneous albinism type 1B (5)
3	-	-	Oculocutaneous albinism (3)
2	-	-	TYR-related disorder (2)
1	-	-	Abnormality of the skin (1)
1	-	-	Albinism or congenital nystagmus (1)
-	1	-	Hearing impairment (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Oculocutaneous albinism type 1A (1)
1	-	-	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 (1)
-	1	-	Oculocutaneous albinism type 1B;C4551504:Oculocutaneous albinism type 1A (1)
1	-	-	Pigmentary skin disorders (1)
1	-	-	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.037	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.4
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.88
MVP		1.0
MPC		0.059
ClinPred		0.020	T
GERP RS		4.7
Varity_R		0.48
gMVP		0.88
Mutation Taster		=70/30	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: rs104894313; hg19: chr11-89017973; COSMIC: COSV99074517;