rs7105971

Variant names:

• chr11-119295337-G-A
• rs7105971
• NM_005188.4:c.2037-1581G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-119295337-G-A
• chr11-119295337-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005188.4(CBL):​c.2037-1581G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 151,910 control chromosomes in the GnomAD database, including 5,135 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5135 hom., cov: 31)
• Consequence: CBL NM_005188.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.35
• Publications: 9 publications found

Genes affected

CBL (HGNC:1541): (Cbl proto-oncogene) This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016]

CBL Gene-Disease associations (from GenCC):

• CBL-related disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Genomics England PanelApp
• juvenile myelomonocytic leukemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBL	NM_005188.4	c.2037-1581G>A		intron_variant	Intron 12 of 15	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6	c.2037-1581G>A		intron_variant	Intron 12 of 15	1	NM_005188.4	ENSP00000264033.3

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38720 AN: 151792 Hom.: 5125 Cov.: 31

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.251

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.255 AC: 38751 AN: 151910 Hom.: 5135 Cov.: 31 AF XY: 0.254 AC XY: 18831 AN XY: 74238

African (AFR) AF: 0.267 AC: 11042 AN: 41380

American (AMR) AF: 0.205 AC: 3124 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1156 AN: 3464

East Asian (EAS) AF: 0.340 AC: 1760 AN: 5170

South Asian (SAS) AF: 0.162 AC: 781 AN: 4822

European-Finnish (FIN) AF: 0.259 AC: 2728 AN: 10520

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17350 AN: 67976

Other (OTH) AF: 0.253 AC: 533 AN: 2108

Alfa AF: 0.256 Hom.: 6209

Bravo AF: 0.254

Asia WGS AF: 0.266 AC: 928 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.077
DANN	Benign	0.72
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs7105971; hg19: chr11-119166047;