12-112418839-G-A

Position:

• chr12-112418839-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000531326.1(PTPN11):​n.331G>A 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 0.0952 in 498,058 control chromosomes in the GnomAD database, including 2,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (957 hom., cov: 33)
  • Exomes 𝑓: 0.091 (1738 hom.)
• Consequence: PTPN11 ENST00000531326.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.486

Genes affected

PTPN11 (HGNC:):

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 12-112418839-G-A is Benign according to our data. Variant chr12-112418839-G-A is described in ClinVar as [Benign]. Clinvar id is 307220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.112418839G>A		intergenic_region
RPL6	NM_001320141.2	c.-340C>T		upstream_gene_variant			NP_001307070.1
RPL6	XM_047429302.1	c.-442C>T		upstream_gene_variant			XP_047285258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000531326.1	n.331G>A		non_coding_transcript_exon_variant	2/2	4
RPL6	ENST00000551291.6	c.-340C>T		upstream_gene_variant		3		ENSP00000448067.2

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15782 AN: 152154 Hom.: 956 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0640

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.106

Gnomad NFE AF: 0.0794

Gnomad OTH AF: 0.0870

GnomAD4 exome AF: 0.0915 AC: 31628 AN: 345786 Hom.: 1738 Cov.: 0 AF XY: 0.0924 AC XY: 16883 AN XY: 182722

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.0582

Gnomad4 ASJ exome AF: 0.0353

Gnomad4 EAS exome AF: 0.173

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.0775

Gnomad4 OTH exome AF: 0.0925

GnomAD4 genome AF: 0.104 AC: 15795 AN: 152272 Hom.: 957 Cov.: 33 AF XY: 0.104 AC XY: 7778 AN XY: 74452

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.0639

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.0794

Gnomad4 OTH AF: 0.0856

Alfa AF: 0.0409 Hom.: 35

Bravo AF: 0.104

Asia WGS AF: 0.214 AC: 743 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Noonan syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

LEOPARD syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Metachondromatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2021

- -

RASopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.9
DANN	Benign	0.93

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs58805176; hg19: chr12-112856643;