chr3-175234070-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_207015.3(NAALADL2):ā€‹c.685A>Gā€‹(p.Ser229Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

NAALADL2
NM_207015.3 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.21
Variant links:
Genes affected
NAALADL2 (HGNC:23219): (N-acetylated alpha-linked acidic dipeptidase like 2) Predicted to enable metalloexopeptidase activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within response to bacterium. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06470981).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NAALADL2NM_207015.3 linkuse as main transcriptc.685A>G p.Ser229Gly missense_variant 3/14 ENST00000454872.6 NP_996898.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NAALADL2ENST00000454872.6 linkuse as main transcriptc.685A>G p.Ser229Gly missense_variant 3/141 NM_207015.3 ENSP00000404705 P1Q58DX5-1
NAALADL2ENST00000485853.5 linkuse as main transcriptn.771A>G non_coding_transcript_exon_variant 3/41
NAALADL2ENST00000473253.5 linkuse as main transcriptn.917A>G non_coding_transcript_exon_variant 3/112
NAALADL2ENST00000489299.5 linkuse as main transcriptn.424A>G non_coding_transcript_exon_variant 3/112

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000322
AC:
8
AN:
248814
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134952
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000232
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461642
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727100
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000227

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 17, 2021The c.685A>G (p.S229G) alteration is located in exon 3 (coding exon 3) of the NAALADL2 gene. This alteration results from a A to G substitution at nucleotide position 685, causing the serine (S) at amino acid position 229 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
Benign
0.068
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0032
T
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.15
FATHMM_MKL
Uncertain
0.79
D
M_CAP
Benign
0.0090
T
MetaRNN
Benign
0.065
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
0.92
N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.015
Sift
Benign
0.25
T
Sift4G
Benign
0.21
T
Polyphen
0.0010
B
Vest4
0.10
MutPred
0.30
Loss of sheet (P = 0.0126);
MVP
0.48
MPC
0.0054
ClinPred
0.21
T
GERP RS
4.4
Varity_R
0.061
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1242391644; hg19: chr3-174951860; API