NM_005468.3:c.1990C>G

Variant names:

• chr11-65045868-G-C
• rs74460041
• NM_005468.3:c.1990C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005468.3(NAALADL1):​c.1990C>G​(p.Arg664Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R664W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAALADL1 NM_005468.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30
• Publications: 3 publications found

Genes affected

NAALADL1 (HGNC:23536): (N-acetylated alpha-linked acidic dipeptidase like 1) Enables aminopeptidase activity; metal ion binding activity; and protein homodimerization activity. Involved in peptide catabolic process. Predicted to be located in apical plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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, 0.961

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005468.3. 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
	NAALADL1	NM_005468.3	MANE Select	c.1990C>G	p.Arg664Gly	missense	Exon 17 of 18	NP_005459.2	Q9UQQ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAALADL1	ENST00000358658.8	TSL:1 MANE Select	c.1990C>G	p.Arg664Gly	missense	Exon 17 of 18	ENSP00000351484.3	Q9UQQ1-1
	NAALADL1	ENST00000528884.5	TSL:1	c.31C>G	p.Arg11Gly	missense	Exon 6 of 6	ENSP00000431513.1	E9PKR0
	NAALADL1	ENST00000528977.5	TSL:1	n.2117C>G		non_coding_transcript_exon	Exon 16 of 17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	0.80
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		2.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.85		Loss of stability (P = 0.0309)
MVP		0.77
MPC		0.76
ClinPred		1.0	D
GERP RS		3.7
PromoterAI		-0.00080	Neutral
Varity_R		0.97
gMVP		0.88
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs74460041; hg19: chr11-64813340;