Genetic Variant NM_207015.3:c.25C>A (chr3-174859432-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_207015.3(NAALADL2):c.25C>A(p.Pro9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NAALADL2
NM_207015.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.17

Publications

0 publications found

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]

NAALADL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22599763).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207015.3. 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
	NAALADL2	NM_207015.3	MANE Select	c.25C>A	p.Pro9Thr	missense	Exon 1 of 14	NP_996898.2	Q58DX5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NAALADL2	ENST00000454872.6	TSL:1 MANE Select	c.25C>A	p.Pro9Thr	missense	Exon 1 of 14	ENSP00000404705.1	Q58DX5-1
NAALADL2	ENST00000485853.5	TSL:1	n.111C>A		non_coding_transcript_exon	Exon 1 of 4
NAALADL2	ENST00000434257.1	TSL:4	c.-9+121686C>A		intron	N/A	ENSP00000409858.1	C9JQ86

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458674

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725422

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33412

American (AMR)

AF:

0.00

AC:

AN:

44370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26022

East Asian (EAS)

AF:

0.00

AC:

AN:

39600

South Asian (SAS)

AF:

0.00

AC:

AN:

85684

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110258

Other (OTH)

AF:

0.00

AC:

AN:

60268

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0014

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.84

M_CAP

Benign

0.0097

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

1.2

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.45

REVEL

Benign

0.18

Sift

Pathogenic

0.0

Sift4G

Benign

0.077

Polyphen

0.91

Vest4

0.43

MutPred

0.12

Gain of sheet (P = 0.0266)

MVP

0.51

MPC

0.018

ClinPred

0.45

GERP RS

5.8

PromoterAI

0.054

Neutral

(source)

Varity_R

0.17

gMVP

0.21

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over