12-70596274-T-C

Variant names:

• chr12-70596274-T-C
• rs2465811
• NM_001109754.4:c.1033A>G

Variant summary

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

The NM_001109754.4(PTPRB):​c.1033A>G​(p.Ser345Gly) variant causes a missense change. The variant allele was found at a frequency of 0.283 in 1,610,220 control chromosomes in the GnomAD database, including 66,100 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.31 (7493 hom., cov: 28)
  • Exomes 𝑓: 0.28 (58607 hom.)
• Consequence: PTPRB NM_001109754.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.00
• Publications: 31 publications found

Genes affected

PTPRB (HGNC:9665): (protein tyrosine phosphatase receptor type B) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular domain, a single transmembrane segment and one intracytoplasmic catalytic domain, thus belongs to receptor type PTP. The extracellular region of this PTP is composed of multiple fibronectin type_III repeats, which was shown to interact with neuronal receptor and cell adhesion molecules, such as contactin and tenascin C. This protein was also found to interact with sodium channels, and thus may regulate sodium channels by altering tyrosine phosphorylation status. The functions of the interaction partners of this protein implicate the roles of this PTP in cell adhesion, neurite growth, and neuronal differentiation. Alternate transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.005496502).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001109754.4. 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
	PTPRB	NM_001109754.4	MANE Select	c.1033A>G	p.Ser345Gly	missense	Exon 5 of 34	NP_001103224.1	P23467-3
	PTPRB	NM_001330204.2		c.1033A>G	p.Ser345Gly	missense	Exon 5 of 33	NP_001317133.1	F8VU56
	PTPRB	NM_002837.6		c.379A>G	p.Ser127Gly	missense	Exon 3 of 32	NP_002828.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPRB	ENST00000334414.11	TSL:1 MANE Select	c.1033A>G	p.Ser345Gly	missense	Exon 5 of 34	ENSP00000334928.6	P23467-3
	PTPRB	ENST00000261266.9	TSL:1	c.379A>G	p.Ser127Gly	missense	Exon 3 of 32	ENSP00000261266.5	P23467-1
	PTPRB	ENST00000538708.5	TSL:1	c.379A>G	p.Ser127Gly	missense	Exon 3 of 31	ENSP00000438927.1	P23467-4

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46315 AN: 150446 Hom.: 7479 Cov.: 28

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.314

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.313

GnomAD2 exomes AF: 0.267 AC: 65929 AN: 246676 AF XY: 0.268

Gnomad AFR exome AF: 0.422

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.296

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.274

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.281 AC: 410063 AN: 1459662 Hom.: 58607 Cov.: 37 AF XY: 0.280 AC XY: 203250 AN XY: 725934

African (AFR) AF: 0.420 AC: 14058 AN: 33440

American (AMR) AF: 0.199 AC: 8853 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6234 AN: 26098

East Asian (EAS) AF: 0.309 AC: 12276 AN: 39670

South Asian (SAS) AF: 0.267 AC: 22936 AN: 85988

European-Finnish (FIN) AF: 0.236 AC: 12531 AN: 53100

Middle Eastern (MID) AF: 0.246 AC: 1418 AN: 5756

European-Non Finnish (NFE) AF: 0.283 AC: 314751 AN: 1110782

Other (OTH) AF: 0.282 AC: 17006 AN: 60292

GnomAD4 genome AF: 0.308 AC: 46365 AN: 150558 Hom.: 7493 Cov.: 28 AF XY: 0.305 AC XY: 22366 AN XY: 73416

African (AFR) AF: 0.416 AC: 17008 AN: 40874

American (AMR) AF: 0.242 AC: 3649 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 846 AN: 3462

East Asian (EAS) AF: 0.314 AC: 1603 AN: 5106

South Asian (SAS) AF: 0.283 AC: 1352 AN: 4774

European-Finnish (FIN) AF: 0.232 AC: 2373 AN: 10230

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18678 AN: 67776

Other (OTH) AF: 0.313 AC: 654 AN: 2088

Alfa AF: 0.286 Hom.: 21105

Bravo AF: 0.313

TwinsUK AF: 0.285 AC: 1055

ALSPAC AF: 0.287 AC: 1108

ESP6500AA AF: 0.397 AC: 1481

ESP6500EA AF: 0.278 AC: 2290

ExAC AF: 0.272 AC: 32791

Asia WGS AF: 0.279 AC: 974 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.037
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.0
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.21
Sift	Uncertain	0.014	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.0070	B
Vest4		0.66
MPC		0.10
ClinPred		0.039	T
GERP RS		5.8
Varity_R		0.25
gMVP		0.59
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2465811; hg19: chr12-70990054; COSMIC: COSV54237760;