11-65045399-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005468.3(NAALADL1):​c.2095G>A​(p.Ala699Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NAALADL1
NM_005468.3 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.08
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NAALADL1NM_005468.3 linkc.2095G>A p.Ala699Thr missense_variant Exon 18 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.2095G>A p.Ala699Thr missense_variant Exon 18 of 18 1 NM_005468.3 ENSP00000351484.3 Q9UQQ1-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460888
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726710
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jun 02, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2095G>A (p.A699T) alteration is located in exon 18 (coding exon 18) of the NAALADL1 gene. This alteration results from a G to A substitution at nucleotide position 2095, causing the alanine (A) at amino acid position 699 to be replaced by a threonine (T). 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
0.20
BayesDel_addAF
Uncertain
0.089
D
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
T;.;.;.;T;.;.;.
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.80
T;T;T;T;T;T;T;T
M_CAP
Benign
0.030
D
MetaRNN
Pathogenic
0.80
D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.43
T
MutationAssessor
Uncertain
2.6
M;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-2.8
D;D;D;D;D;D;D;D
REVEL
Uncertain
0.35
Sift
Benign
0.038
D;T;T;D;D;T;T;D
Sift4G
Benign
0.066
T;D;T;T;T;T;T;.
Polyphen
0.97
D;.;.;.;.;.;.;.
Vest4
0.25
MutPred
0.75
Gain of phosphorylation at A699 (P = 0.0546);.;.;.;.;.;.;.;
MVP
0.60
MPC
0.61
ClinPred
0.98
D
GERP RS
3.6
Varity_R
0.70
gMVP
0.73

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

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

Other links and lift over

dbSNP: rs1946695298; hg19: chr11-64812871; API