11-65045868-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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 (★).

• 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

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAALADL1	NM_005468.3	c.1990C>G	p.Arg664Gly	missense_variant	Exon 17 of 18	ENST00000358658.8	NP_005459.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAALADL1	ENST00000358658.8	c.1990C>G	p.Arg664Gly	missense_variant	Exon 17 of 18	1	NM_005468.3	ENSP00000351484.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1990C>G (p.R664G) alteration is located in exon 17 (coding exon 17) of the NAALADL1 gene. This alteration results from a C to G substitution at nucleotide position 1990, causing the arginine (R) at amino acid position 664 to be replaced by a glycine (G). 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	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;.;.;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.4	.;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.0	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;T;D;D;D;T;D;D;.;D;D;D
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.
Vest4		0.94, 0.97, 0.94, 0.94, 0.82
MutPred		0.85		.;Loss of stability (P = 0.0309);.;.;.;.;.;.;.;.;.;.;
MVP		0.77
MPC		0.76
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.97
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs74460041; hg19: chr11-64813340;