chr11-119309606-G-A

Variant names:

• chr11-119309606-G-A
• rs7914
• NM_006500.3:c.*280C>T

Variant summary

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

The NM_006500.3(MCAM):​c.*280C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 515,812 control chromosomes in the GnomAD database, including 23,025 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 0.29 (6752 hom., cov: 33)
  • Exomes 𝑓: 0.28 (16273 hom.)
• Consequence: MCAM NM_006500.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.182
• Publications: 23 publications found

Genes affected

MCAM (HGNC:6934): (melanoma cell adhesion molecule) Involved in glomerular filtration and vascular wound healing. Acts upstream of or within angiogenesis. Located in external side of plasma membrane. Biomarker of chronic obstructive pulmonary disease and uveal melanoma. [provided by Alliance of Genome Resources, Apr 2022]

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=-0.71).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006500.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCAM	NM_006500.3	MANE Select	c.*280C>T		3_prime_UTR	Exon 16 of 16	NP_006491.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCAM	ENST00000264036.6	TSL:1 MANE Select	c.*280C>T		3_prime_UTR	Exon 16 of 16	ENSP00000264036.4
	MCAM	ENST00000528533.5	TSL:5	n.2530C>T		non_coding_transcript_exon	Exon 14 of 14
	CBL	ENST00000637974.1	TSL:5	c.2522-3812G>A		intron	N/A	ENSP00000490763.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43725 AN: 151990 Hom.: 6748 Cov.: 33

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.274

GnomAD4 exome AF: 0.278 AC: 101013 AN: 363704 Hom.: 16273 Cov.: 0 AF XY: 0.290 AC XY: 55022 AN XY: 189798

African (AFR) AF: 0.363 AC: 3988 AN: 10984

American (AMR) AF: 0.285 AC: 3904 AN: 13700

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 3239 AN: 11520

East Asian (EAS) AF: 0.423 AC: 11299 AN: 26716

South Asian (SAS) AF: 0.520 AC: 16419 AN: 31594

European-Finnish (FIN) AF: 0.228 AC: 5614 AN: 24612

Middle Eastern (MID) AF: 0.286 AC: 464 AN: 1620

European-Non Finnish (NFE) AF: 0.226 AC: 50151 AN: 221436

Other (OTH) AF: 0.276 AC: 5935 AN: 21522

GnomAD4 genome AF: 0.288 AC: 43768 AN: 152108 Hom.: 6752 Cov.: 33 AF XY: 0.292 AC XY: 21746 AN XY: 74354

African (AFR) AF: 0.351 AC: 14548 AN: 41468

American (AMR) AF: 0.298 AC: 4566 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 963 AN: 3472

East Asian (EAS) AF: 0.456 AC: 2354 AN: 5160

South Asian (SAS) AF: 0.546 AC: 2632 AN: 4824

European-Finnish (FIN) AF: 0.213 AC: 2258 AN: 10582

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15675 AN: 67986

Other (OTH) AF: 0.274 AC: 579 AN: 2112

Alfa AF: 0.263 Hom.: 10826

Bravo AF: 0.293

Asia WGS AF: 0.498 AC: 1730 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.6
DANN	Benign	0.84
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7914; hg19: chr11-119180316;