11-65045867-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005468.3(NAALADL1):​c.1991G>A​(p.Arg664Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,986 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R664G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 1 hom. )

Consequence

NAALADL1
NM_005468.3 missense

Scores

10
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.44
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.954

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NAALADL1NM_005468.3 linkc.1991G>A p.Arg664Gln missense_variant Exon 17 of 18 ENST00000358658.8 NP_005459.2 Q9UQQ1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NAALADL1ENST00000358658.8 linkc.1991G>A p.Arg664Gln missense_variant Exon 17 of 18 1 NM_005468.3 ENSP00000351484.3 Q9UQQ1-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251322
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135858
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461822
Hom.:
1
Cov.:
32
AF XY:
0.0000124
AC XY:
9
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000928
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152164
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000936
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 22, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1991G>A (p.R664Q) alteration is located in exon 17 (coding exon 17) of the NAALADL1 gene. This alteration results from a G to A substitution at nucleotide position 1991, causing the arginine (R) at amino acid position 664 to be replaced by a glutamine (Q). 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
Benign
0.26
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.26
.;T;.;.;.;T;.;.;.;.;.;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.090
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Pathogenic
3.4
.;M;.;.;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-4.0
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;.;D;D;D
Polyphen
1.0
.;D;.;.;.;.;.;.;.;.;.;.
Vest4
0.78, 0.95, 0.79, 0.81, 0.82, 0.68
MutPred
0.84
.;Loss of phosphorylation at T665 (P = 0.2314);.;.;.;.;.;.;.;.;.;.;
MVP
0.77
MPC
0.69
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.94
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs746281476; hg19: chr11-64813339; API