Genetic Variant CMAS:p.Gly54Val (chr12-22046464-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_018686.6(CMAS):c.161G>T(p.Gly54Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G54D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CMAS
NM_018686.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.59

Publications

0 publications found

Variant links:

Genes affected

CMAS (HGNC:18290): (cytidine monophosphate N-acetylneuraminic acid synthetase) This gene encodes an enzyme that converts N-acetylneuraminic acid (NeuNAc) to cytidine 5'-monophosphate N-acetylneuraminic acid (CMP-NeuNAc). This process is important in the formation of sialylated glycoprotein and glycolipids. This modification plays a role in cell-cell communications and immune responses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

CMAS Gene-Disease associations (from GenCC):

intellectual disability
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

CMAS links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMAS	NM_018686.6 link	c.161G>T	p.Gly54Val	missense_variant	Exon 1 of 8	ENST00000229329.7	NP_061156.1	Q8NFW8-1
CMAS	NR_135117.2 link	n.247G>T		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CMAS	ENST00000229329.7 link	c.161G>T	p.Gly54Val	missense_variant	Exon 1 of 8	1	NM_018686.6	ENSP00000229329.2	Q8NFW8-1
CMAS	ENST00000534981.5 link	n.161G>T		non_coding_transcript_exon_variant	Exon 1 of 7	1		ENSP00000446239.1	Q8NFW8-2
CMAS	ENST00000535610.5 link	n.161G>T		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000439404.1	F5H296

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457938

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725038

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33216

American (AMR)

AF:

0.00

AC:

AN:

44306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25952

East Asian (EAS)

AF:

0.00

AC:

AN:

39474

South Asian (SAS)

AF:

0.00

AC:

AN:

85272

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53084

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110690

Other (OTH)

AF:

0.0000166

AC:

AN:

60192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

4.5

PhyloP100

8.6

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-8.1

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.75

MutPred

0.85

Loss of disorder (P = 0.052);

MVP

0.65

MPC

2.1

ClinPred

1.0

GERP RS

4.7

PromoterAI

-0.0016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.96

gMVP

0.84

Mutation Taster

=32/68

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over