rs58805176

Variant names:

• chr12-112418839-G-A
• rs58805176
• ENST00000955984.1:c.-1368C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-112418839-G-A
• chr12-112418839-G-C
• chr12-112418839-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000955984.1(RPL6):​c.-1368C>T variant causes a 5 prime UTR premature start codon gain 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: RPL6 ENST00000955984.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.486
• Publications: 5 publications found

Genes affected

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]

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]

PTPN11 Gene-Disease associations (from GenCC):

• LEOPARD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• metachondromatosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000955984.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	NM_002834.5	MANE Select	c.-273G>A		upstream_gene	N/A	NP_002825.3
	PTPN11	NM_001330437.2		c.-273G>A		upstream_gene	N/A	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.-273G>A		upstream_gene	N/A	NP_001361554.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL6	ENST00000955984.1		c.-1368C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000626043.1
	RPL6	ENST00000955984.1		c.-1368C>T		5_prime_UTR	Exon 1 of 9	ENSP00000626043.1
	PTPN11	ENST00000531326.1	TSL:4	n.331G>A		non_coding_transcript_exon	Exon 2 of 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

African (AFR) AF: 0.142 AC: 1065 AN: 7496

American (AMR) AF: 0.0582 AC: 462 AN: 7944

Ashkenazi Jewish (ASJ) AF: 0.0353 AC: 388 AN: 10992

East Asian (EAS) AF: 0.173 AC: 3878 AN: 22376

South Asian (SAS) AF: 0.127 AC: 4330 AN: 34192

European-Finnish (FIN) AF: 0.109 AC: 2797 AN: 25770

Middle Eastern (MID) AF: 0.0958 AC: 157 AN: 1638

European-Non Finnish (NFE) AF: 0.0775 AC: 16614 AN: 214446

Other (OTH) AF: 0.0925 AC: 1937 AN: 20932

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

African (AFR) AF: 0.149 AC: 6177 AN: 41568

American (AMR) AF: 0.0639 AC: 977 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3470

East Asian (EAS) AF: 0.234 AC: 1206 AN: 5154

South Asian (SAS) AF: 0.130 AC: 627 AN: 4834

European-Finnish (FIN) AF: 0.101 AC: 1074 AN: 10616

Middle Eastern (MID) AF: 0.100 AC: 29 AN: 290

European-Non Finnish (NFE) AF: 0.0794 AC: 5404 AN: 68020

Other (OTH) AF: 0.0856 AC: 181 AN: 2114

Alfa AF: 0.0444 Hom.: 46

Bravo AF: 0.104

Asia WGS AF: 0.214 AC: 743 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (1)
-	-	1	LEOPARD syndrome 1 (1)
-	-	1	Metachondromatosis (1)
-	-	1	Noonan syndrome 1 (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.9
DANN	Benign	0.93
PhyloP100		-0.49
PromoterAI		0.29	Neutral

Splicing

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

Other links and lift over

dbSNP: rs58805176; hg19: chr12-112856643;