chr12-70524555-C-T

Variant names:

• chr12-70524555-C-T
• rs1293785543
• NM_001109754.4:c.6541G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001109754.4(PTPRB):​c.6541G>A​(p.Val2181Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTPRB NM_001109754.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 1 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]

PTPRB-AS1 (HGNC:58150):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38828528).

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.6541G>A	p.Val2181Ile	missense	Exon 33 of 34	NP_001103224.1	P23467-3
	PTPRB	NM_001330204.2		c.6277G>A	p.Val2093Ile	missense	Exon 32 of 33	NP_001317133.1	F8VU56
	PTPRB	NM_002837.6		c.5887G>A	p.Val1963Ile	missense	Exon 31 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.6541G>A	p.Val2181Ile	missense	Exon 33 of 34	ENSP00000334928.6	P23467-3
	PTPRB	ENST00000261266.9	TSL:1	c.5887G>A	p.Val1963Ile	missense	Exon 31 of 32	ENSP00000261266.5	P23467-1
	PTPRB	ENST00000538708.5	TSL:1	c.5617G>A	p.Val1873Ile	missense	Exon 30 of 31	ENSP00000438927.1	P23467-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460754 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726720

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111108

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.47	N
PhyloP100		7.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.70	N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.075	T
Polyphen		1.0	D
Vest4		0.56
MutPred		0.39		Loss of helix (P = 0.079)
MVP		0.30
MPC		1.1
ClinPred		0.91	D
GERP RS		5.7
Varity_R		0.68
gMVP		0.42
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1293785543; hg19: chr12-70918335;