Genetic Variant NAALADL1:p.Thr692Lys (chr11-65045419-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005468.3(NAALADL1):c.2075C>A(p.Thr692Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T692I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NAALADL1
NM_005468.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.19

Publications

1 publications found

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]

NAALADL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.902

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005468.3. 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
	NAALADL1	NM_005468.3	MANE Select	c.2075C>A	p.Thr692Lys	missense	Exon 18 of 18	NP_005459.2	Q9UQQ1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NAALADL1	ENST00000358658.8	TSL:1 MANE Select	c.2075C>A	p.Thr692Lys	missense	Exon 18 of 18	ENSP00000351484.3	Q9UQQ1-1
NAALADL1	ENST00000528977.5	TSL:1	n.2202C>A		non_coding_transcript_exon	Exon 17 of 17
NAALADL1	ENST00000529274.5	TSL:1	n.2244C>A		non_coding_transcript_exon	Exon 15 of 15

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000803

AC:

AN:

248930

AF XY:

0.00000741

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460586

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52868

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111634

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.90

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.6

PhyloP100

7.2

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.46

Sift

Uncertain

0.0020

Sift4G

Benign

0.20

Polyphen

0.80

Vest4

0.63

MutPred

0.77

Gain of methylation at T692 (P = 0.0168)

MVP

0.79

MPC

0.73

ClinPred

0.90

GERP RS

4.6

Varity_R

0.93

gMVP

0.81

Mutation Taster

=46/54

disease causing

(source)

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

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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