dbSNP rs1822581744: CARNMT1:p.Gly77Asp (chr9-75028012-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_152420.3(CARNMT1):c.230G>A(p.Gly77Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CARNMT1
NM_152420.3 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.73

Publications

0 publications found

Variant links:

Genes affected

CARNMT1 (HGNC:23435): (carnosine N-methyltransferase 1) The protein encoded by this gene is a methyltransferase that converts carnosine to anserine, a dipeptide found abundantly in skeletal muscle. The encoded protein can methylate other dipeptides as well. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

CARNMT1 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;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.8756 (below the threshold of 3.09). Trascript score misZ: 0.3004 (below the threshold of 3.09).

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 9-75028012-C-T is Pathogenic according to our data. Variant chr9-75028012-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 996578.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152420.3. 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
	CARNMT1	NM_152420.3	MANE Select	c.230G>A	p.Gly77Asp	missense splice_region	Exon 1 of 8	NP_689633.1	Q8N4J0
	CARNMT1	NR_135282.1		n.419G>A		splice_region non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CARNMT1	ENST00000376834.8	TSL:1 MANE Select	c.230G>A	p.Gly77Asp	missense splice_region	Exon 1 of 8	ENSP00000366030.3	Q8N4J0
CARNMT1	ENST00000376830.3	TSL:1	c.230G>A	p.Gly77Asp	missense splice_region	Exon 1 of 2	ENSP00000366026.3	Q5T8U9
CARNMT1	ENST00000928755.1		c.230G>A	p.Gly77Asp	missense splice_region	Exon 1 of 9	ENSP00000598814.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1415130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703256

African (AFR)

AF:

0.00

AC:

AN:

28984

American (AMR)

AF:

0.00

AC:

AN:

39690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24668

East Asian (EAS)

AF:

0.00

AC:

AN:

33532

South Asian (SAS)

AF:

0.00

AC:

AN:

81664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50718

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091930

Other (OTH)

AF:

0.00

AC:

AN:

58294

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.046

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.82

PhyloP100

2.7

PROVEAN

Benign

-1.9

REVEL

Benign

0.19

Sift

Benign

0.57

Sift4G

Benign

0.50

Polyphen

0.89

Vest4

0.63

MutPred

0.55

Loss of methylation at R74 (P = 0.046)

MVP

0.068

MPC

0.28

ClinPred

0.93

GERP RS

5.3

PromoterAI

-0.38

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.67

Mutation Taster

=38/62

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.15

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over