9-74984975-C-T

Variant names:

• chr9-74984975-C-T
• NM_152420.3:c.1060G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_152420.3(CARNMT1):​c.1060G>A​(p.Glu354Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CARNMT1 NM_152420.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.20
• Publications: 0 publications found

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-AS1 (HGNC:51188): (CARNMT1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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).

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.1060G>A	p.Glu354Lys	missense	Exon 7 of 8	NP_689633.1	Q8N4J0
	CARNMT1	NM_001320497.2		c.823G>A	p.Glu275Lys	missense	Exon 7 of 8	NP_001307426.1
	CARNMT1	NR_135282.1		n.1108G>A		non_coding_transcript_exon	Exon 6 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARNMT1	ENST00000376834.8	TSL:1 MANE Select	c.1060G>A	p.Glu354Lys	missense	Exon 7 of 8	ENSP00000366030.3	Q8N4J0
	CARNMT1-AS1	ENST00000455609.2	TSL:1	n.249-6190C>T		intron	N/A
	CARNMT1	ENST00000928755.1		c.1135G>A	p.Glu379Lys	missense	Exon 8 of 9	ENSP00000598814.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-1.1	T
PhyloP100		6.2
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.63		Gain of ubiquitination at E354 (P = 0.0138)
MVP		0.16
MPC		2.5
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.68
gMVP		0.92
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr9-77599891;