12-6951603-G-A

Position:

• chr12-6951603-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002831.6(PTPN6):​c.9-6G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,613,900 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: PTPN6 NM_002831.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007374
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.57

Genes affected

PTPN6 (HGNC:9658): (protein tyrosine phosphatase non-receptor type 6) 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. N-terminal part of this PTP contains two tandem Src homolog (SH2) domains, which act as protein phospho-tyrosine binding domains, and mediate the interaction of this PTP with its substrates. This PTP is expressed primarily in hematopoietic cells, and functions as an important regulator of multiple signaling pathways in hematopoietic cells. This PTP has been shown to interact with, and dephosphorylate a wide spectrum of phospho-proteins involved in hematopoietic cell signaling. Multiple alternatively spliced variants of this gene, which encode distinct isoforms, have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-6951603-G-A is Benign according to our data. Variant chr12-6951603-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 626002.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 315 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN6	NM_002831.6	c.9-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000318974.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN6	ENST00000318974.14	c.9-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002831.6	P1

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152022 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.0626

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00185 AC: 461 AN: 249222 Hom.: 2 AF XY: 0.00203 AC XY: 275 AN XY: 135338

Gnomad AFR exome AF: 0.000647

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00225

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00270

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00252 AC: 3680 AN: 1461760 Hom.: 5 Cov.: 31 AF XY: 0.00252 AC XY: 1836 AN XY: 727174

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00183

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.00286

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152140 Hom.: 4 Cov.: 32 AF XY: 0.00190 AC XY: 141 AN XY: 74374

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00290

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00201

Asia WGS AF: 0.000866 AC: 6 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	PTPN6 NM_080549.3 intron 2 c.9-6G>A: This variant has not been reported in the literature but has been identified by our institution in 1 individual with neutropenia. This variant is present in 0.2% (69/30602) of South Asian alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-7060766-G-A?dataset=gnomad_r2_1). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant; splice prediction tools suggest that this variant may not affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.42
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000074
dbscSNV1_RF	Benign	0.0020
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: rs200900053; hg19: chr12-7060766;