12-70539627-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001109754.4(PTPRB):c.5776G>C(p.Glu1926Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000349 in 1,546,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: PTPRB NM_001109754.4 missense, splice_region
• Scores: Splicing: ADA: 0.9573
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PTPRB
• BP4: Computational evidence support a benign effect (MetaRNN=0.2621001).
• BS2: High AC in GnomAdExome at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPRB	NM_001109754.4	c.5776G>C	p.Glu1926Gln	missense_variant, splice_region_variant	26/34	ENST00000334414.11
LOC105369828	XR_001749196.2	n.10006+11889C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPRB	ENST00000334414.11	c.5776G>C	p.Glu1926Gln	missense_variant, splice_region_variant	26/34	1	NM_001109754.4	A1
	ENST00000548687.5	n.2490C>G		non_coding_transcript_exon_variant	9/9	1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000788 AC: 15 AN: 190420 Hom.: 0 AF XY: 0.0000888 AC XY: 9 AN XY: 101348

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000109

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000359 AC: 50 AN: 1394012 Hom.: 0 Cov.: 30 AF XY: 0.0000304 AC XY: 21 AN XY: 691244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000588

Gnomad4 NFE exome AF: 0.0000385

Gnomad4 OTH exome AF: 0.000103

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000167 AC: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2023

The c.5776G>C (p.E1926Q) alteration is located in exon 26 (coding exon 26) of the PTPRB gene. This alteration results from a G to C substitution at nucleotide position 5776, causing the glutamic acid (E) at amino acid position 1926 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.37
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.6	D;D;D;D;N
REVEL	Benign	0.22
Sift	Uncertain	0.0090	D;D;D;D;D
Sift4G	Uncertain	0.027	D;D;T;T;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.40
MVP		0.52
MPC		1.2
ClinPred		0.46	T
GERP RS		5.8
Varity_R		0.52
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.67
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

Publications

LitVar

Other links and lift over

dbSNP: rs750869262; hg19: chr12-70933407; COSMIC: COSV54239121; COSMIC: COSV54239121;