12-6957776-G-A

Position:

• chr12-6957776-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002831.6(PTPN6):​c.1197G>A​(p.Pro399=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,614,124 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (20 hom.)
• Consequence: PTPN6 NM_002831.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -6.31

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-6957776-G-A is Benign according to our data. Variant chr12-6957776-G-A is described in ClinVar as [Benign]. Clinvar id is 778582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0118 (1795/152332) while in subpopulation AFR AF= 0.0388 (1611/41562). AF 95% confidence interval is 0.0372. There are 23 homozygotes in gnomad4. There are 871 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1795 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN6	NM_002831.6	c.1197G>A	p.Pro399=	synonymous_variant	10/16	ENST00000318974.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN6	ENST00000318974.14	c.1197G>A	p.Pro399=	synonymous_variant	10/16	1	NM_002831.6	P1
PTPN6	ENST00000456013.5	c.1197G>A	p.Pro399=	synonymous_variant	10/16	1
PTPN6	ENST00000399448.5	c.1203G>A	p.Pro401=	synonymous_variant	10/16	1
PTPN6	ENST00000416215.6	n.1605G>A		non_coding_transcript_exon_variant	9/15	2

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1791 AN: 152214 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00352 AC: 878 AN: 249246 Hom.: 6 AF XY: 0.00270 AC XY: 366 AN XY: 135326

Gnomad AFR exome AF: 0.0352

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000425

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00155 AC: 2262 AN: 1461792 Hom.: 20 Cov.: 36 AF XY: 0.00139 AC XY: 1011 AN XY: 727200

Gnomad4 AFR exome AF: 0.0337

Gnomad4 AMR exome AF: 0.00324

Gnomad4 ASJ exome AF: 0.0170

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000245

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.0118 AC: 1795 AN: 152332 Hom.: 23 Cov.: 32 AF XY: 0.0117 AC XY: 871 AN XY: 74498

Gnomad4 AFR AF: 0.0388

Gnomad4 AMR AF: 0.00569

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00506 Hom.: 6

Bravo AF: 0.0130

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.42
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116298095; hg19: chr12-7066939;