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. 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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPRB	NM_001109754.4	c.1033A>G	p.Ser345Gly	missense_variant	Exon 5 of 34	ENST00000334414.11	NP_001103224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPRB	ENST00000334414.11	c.1033A>G	p.Ser345Gly	missense_variant	Exon 5 of 34	1	NM_001109754.4	ENSP00000334928.6

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

Gnomad4 AFR exome AF: 0.420 AC: 14058 AN: 33440

Gnomad4 AMR exome AF: 0.199 AC: 8853 AN: 44536

Gnomad4 ASJ exome AF: 0.239 AC: 6234 AN: 26098

Gnomad4 EAS exome AF: 0.309 AC: 12276 AN: 39670

Gnomad4 SAS exome AF: 0.267 AC: 22936 AN: 85988

Gnomad4 FIN exome AF: 0.236 AC: 12531 AN: 53100

Gnomad4 NFE exome AF: 0.283 AC: 314751 AN: 1110782

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.416 AC: 0.416108 AN: 0.416108

Gnomad4 AMR AF: 0.242 AC: 0.242491 AN: 0.242491

Gnomad4 ASJ AF: 0.244 AC: 0.244367 AN: 0.244367

Gnomad4 EAS AF: 0.314 AC: 0.313944 AN: 0.313944

Gnomad4 SAS AF: 0.283 AC: 0.283201 AN: 0.283201

Gnomad4 FIN AF: 0.232 AC: 0.231965 AN: 0.231965

Gnomad4 NFE AF: 0.276 AC: 0.275584 AN: 0.275584

Gnomad4 OTH AF: 0.313 AC: 0.313218 AN: 0.313218

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;T;.;.;T;T;T
Eigen	Benign	-0.037
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	T;T;T;T;T;T;T
MetaRNN	Benign	0.0055	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	.;.;M;M;M;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.014	D;D;D;T;T;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		0.0070	B;B;.;B;B;B;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

Publications

LitVar

Other links and lift over

dbSNP: rs2465811; hg19: chr12-70990054; COSMIC: COSV54237760;