rs1466684

Variant names:

• chr3-151328520-G-A
• rs1466684
• NM_176894.3:c.536C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_176894.3(P2RY13):​c.536C>T​(p.Thr179Met) variant causes a missense change. The variant allele was found at a frequency of 0.842 in 1,613,500 control chromosomes in the GnomAD database, including 573,196 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.87 (58239 hom., cov: 31)
  • Exomes 𝑓: 0.84 (514957 hom.)
• Consequence: P2RY13 NM_176894.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• Publications: 43 publications found

Genes affected

P2RY13 (HGNC:4537): (purinergic receptor P2Y13) The product of this gene belongs to the family of G-protein coupled receptors. This family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. This receptor is activated by ADP. [provided by RefSeq, Sep 2008]

MED12L (HGNC:16050): (mediator complex subunit 12L) The protein encoded by this gene is part of the Mediator complex, which is involved in transcriptional coactivation of nearly all RNA polymerase II-dependent genes. The Mediator complex links gene-specific transcriptional activators with the basal transcription machinery. [provided by RefSeq, May 2010]

MED12L Gene-Disease associations (from GenCC):

• Nizon-Isidor syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.1681396E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176894.3. 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
	P2RY13	NM_176894.3	MANE Select	c.536C>T	p.Thr179Met	missense	Exon 2 of 2	NP_795713.2	Q9BPV8-1
	MED12L	NM_001393769.1	MANE Select	c.2251-21539G>A		intron	N/A	NP_001380698.1	A0A8I5KX78
	MED12L	NM_053002.6		c.2146-21539G>A		intron	N/A	NP_443728.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RY13	ENST00000325602.6	TSL:1 MANE Select	c.536C>T	p.Thr179Met	missense	Exon 2 of 2	ENSP00000320376.5	Q9BPV8-1
	MED12L	ENST00000687756.1	MANE Select	c.2251-21539G>A		intron	N/A	ENSP00000508695.1	A0A8I5KX78
	MED12L	ENST00000474524.5	TSL:1	c.2146-21539G>A		intron	N/A	ENSP00000417235.1	Q86YW9-1

Frequencies

GnomAD3 genomes AF: 0.873 AC: 132777 AN: 152036 Hom.: 58189 Cov.: 31

Gnomad AFR AF: 0.952

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.874

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.902

Gnomad FIN AF: 0.842

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.830

Gnomad OTH AF: 0.897

GnomAD2 exomes AF: 0.861 AC: 215710 AN: 250402 AF XY: 0.862

Gnomad AFR exome AF: 0.953

Gnomad AMR exome AF: 0.889

Gnomad ASJ exome AF: 0.883

Gnomad EAS exome AF: 0.843

Gnomad FIN exome AF: 0.841

Gnomad NFE exome AF: 0.834

Gnomad OTH exome AF: 0.855

GnomAD4 exome AF: 0.839 AC: 1225515 AN: 1461346 Hom.: 514957 Cov.: 50 AF XY: 0.841 AC XY: 611491 AN XY: 726984

African (AFR) AF: 0.959 AC: 32083 AN: 33472

American (AMR) AF: 0.889 AC: 39704 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.881 AC: 23022 AN: 26136

East Asian (EAS) AF: 0.839 AC: 33284 AN: 39694

South Asian (SAS) AF: 0.900 AC: 77611 AN: 86254

European-Finnish (FIN) AF: 0.839 AC: 44802 AN: 53406

Middle Eastern (MID) AF: 0.950 AC: 5477 AN: 5768

European-Non Finnish (NFE) AF: 0.826 AC: 917876 AN: 1111562

Other (OTH) AF: 0.856 AC: 51656 AN: 60380

GnomAD4 genome AF: 0.873 AC: 132889 AN: 152154 Hom.: 58239 Cov.: 31 AF XY: 0.875 AC XY: 65050 AN XY: 74376

African (AFR) AF: 0.952 AC: 39521 AN: 41510

American (AMR) AF: 0.875 AC: 13365 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 3048 AN: 3472

East Asian (EAS) AF: 0.848 AC: 4386 AN: 5170

South Asian (SAS) AF: 0.901 AC: 4344 AN: 4820

European-Finnish (FIN) AF: 0.842 AC: 8912 AN: 10586

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.830 AC: 56469 AN: 68000

Other (OTH) AF: 0.893 AC: 1886 AN: 2112

Alfa AF: 0.847 Hom.: 234699

Bravo AF: 0.880

TwinsUK AF: 0.823 AC: 3050

ALSPAC AF: 0.814 AC: 3136

ESP6500AA AF: 0.948 AC: 4175

ESP6500EA AF: 0.833 AC: 7160

ExAC AF: 0.863 AC: 104815

Asia WGS AF: 0.845 AC: 2941 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.71
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	6.2e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.2	N
PhyloP100		5.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	3.2	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	0.96	T
Polyphen		0.0010	B
Vest4		0.035
MPC		0.10
ClinPred		0.0062	T
GERP RS		4.3
Varity_R		0.021
gMVP		0.42
Mutation Taster		=99/1	polymorphism (auto)

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: rs1466684; hg19: chr3-151046308; COSMIC: COSV56380424;