rs61754398

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 4 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• 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: Likely_benign. The variant received -5 ACMG points.

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

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.1366+4A>G		splice_region intron	N/A	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.1366+4A>G		splice_region intron	N/A	ENSP00000263321.4	P14679-1
	TYR	ENST00000528243.1	TSL:5	n.364+4A>G		splice_region intron	N/A

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

GnomAD2 exomes AF: 0.00150 AC: 374 AN: 249624 AF XY: 0.00141

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 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

African (AFR) AF: 0.000270 AC: 9 AN: 33306

American (AMR) AF: 0.000180 AC: 8 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86180

European-Finnish (FIN) AF: 0.00105 AC: 56 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00303 AC: 3362 AN: 1109336

Other (OTH) AF: 0.00140 AC: 84 AN: 60196

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

African (AFR) AF: 0.000482 AC: 20 AN: 41520

American (AMR) AF: 0.000919 AC: 14 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00292 AC: 198 AN: 67870

Other (OTH) AF: 0.00190 AC: 4 AN: 2104

Alfa AF: 0.00188 Hom.: 0

Bravo AF: 0.00135

EpiCase AF: 0.00191

EpiControl AF: 0.00225

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (5)
-	1	-	not specified (1)
-	1	-	Oculocutaneous albinism (1)
-	1	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	16
DANN	Benign	0.57
PhyloP100		3.7
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs61754398; hg19: chr11-89018126;