11-119310449-C-T

Position:

chr11-119310449-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006500.3(MCAM):c.1811G>A(p.Arg604His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,613,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

MCAM
NM_006500.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.697

Variant links:

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]

MCAM links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19664031).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCAM	NM_006500.3 linkuse as main transcript	c.1811G>A	p.Arg604His	missense_variant	15/16	ENST00000264036.6	NP_006491.2	P43121-1A0A024R3I5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCAM	ENST00000264036.6 linkuse as main transcript	c.1811G>A	p.Arg604His	missense_variant	15/16	1	NM_006500.3	ENSP00000264036.4		P43121-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251348

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000760

AC:

111

AN:

1460732

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

726756

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000819

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000100

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.1811G>A (p.R604H) alteration is located in exon 15 (coding exon 15) of the MCAM gene. This alteration results from a G to A substitution at nucleotide position 1811, causing the arginine (R) at amino acid position 604 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

0.12

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.71

M_CAP

Benign

0.030

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.69

REVEL

Benign

0.080

Sift

Uncertain

0.028

Sift4G

Uncertain

0.050

Polyphen

0.99

Vest4

0.20

MVP

0.60

MPC

0.26

ClinPred

0.10

GERP RS

3.4

Varity_R

0.047

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over