12-112418795-C-T

Variant names:

• chr12-112418795-C-T
• rs373537430
• ENST00000531326.1:n.287C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000531326.1(PTPN11):​n.287C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 452,704 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PTPN11 ENST00000531326.1 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.970
• Publications: 1 publications found

Genes affected

PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) 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 two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

RPL6 (HGNC:10362): (ribosomal protein L6) This gene encodes a protein component of the 60S ribosomal subunit. This protein can bind specifically to domain C of the tax-responsive enhancer element of human T-cell leukemia virus type 1, and may participate in tax-mediated transactivation of transcription. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed throughout the genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-112418795-C-T is Benign according to our data. Variant chr12-112418795-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 695270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000236 (36/152354) while in subpopulation EAS AF = 0.0062 (32/5164). AF 95% confidence interval is 0.00451. There are 1 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.-317C>T		upstream_gene_variant		ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.-317C>T		upstream_gene_variant		1	NM_002834.5	ENSP00000340944.3

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 36 AN: 152236 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00618

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000133 AC: 40 AN: 300350 Hom.: 0 Cov.: 0 AF XY: 0.000134 AC XY: 21 AN XY: 157230

African (AFR) AF: 0.00 AC: 0 AN: 6640

American (AMR) AF: 0.00 AC: 0 AN: 6156

Ashkenazi Jewish (ASJ) AF: 0.000501 AC: 5 AN: 9990

East Asian (EAS) AF: 0.00138 AC: 27 AN: 19628

South Asian (SAS) AF: 0.0000634 AC: 2 AN: 31522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1448

European-Non Finnish (NFE) AF: 0.0000108 AC: 2 AN: 184788

Other (OTH) AF: 0.000215 AC: 4 AN: 18576

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152354 Hom.: 1 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74500

African (AFR) AF: 0.00 AC: 0 AN: 41600

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00620 AC: 32 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000223

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTPN11: BS1 -

RASopathy Benign:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.9
DANN	Benign	0.87
PhyloP100		-0.97
PromoterAI		0.0081	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs373537430; hg19: chr12-112856599;