3-175097119-G-A

Variant names:

• chr3-175097119-G-A
• rs150099163
• NM_207015.3:c.373G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_207015.3(NAALADL2):​c.373G>A​(p.Val125Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00464 in 1,613,652 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (47 hom.)
• Consequence: NAALADL2 NM_207015.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.118
• Publications: 7 publications found

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-AS3 (HGNC:41014): (NAALADL2 antisense RNA 3)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059213936).
• BP6: Variant 3-175097119-G-A is Benign according to our data. Variant chr3-175097119-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2654282.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00484 (7080/1461472) while in subpopulation MID AF = 0.0205 (118/5766). AF 95% confidence interval is 0.0175. There are 47 homozygotes in GnomAdExome4. There are 3614 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 47 AR gene

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.373G>A	p.Val125Ile	missense	Exon 2 of 14	NP_996898.2	Q58DX5-1
	NAALADL2-AS3	NR_046390.1		n.110+15425C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAALADL2	ENST00000454872.6	TSL:1 MANE Select	c.373G>A	p.Val125Ile	missense	Exon 2 of 14	ENSP00000404705.1	Q58DX5-1
	NAALADL2	ENST00000485853.5	TSL:1	n.459G>A		non_coding_transcript_exon	Exon 2 of 4
	NAALADL2	ENST00000434257.1	TSL:4	c.322G>A	p.Val108Ile	missense	Exon 4 of 4	ENSP00000409858.1	C9JQ86

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 409 AN: 152062 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00706

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00374 AC: 932 AN: 248914 AF XY: 0.00415

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.000975

Gnomad NFE exome AF: 0.00479

Gnomad OTH exome AF: 0.00431

GnomAD4 exome AF: 0.00484 AC: 7080 AN: 1461472 Hom.: 47 Cov.: 35 AF XY: 0.00497 AC XY: 3614 AN XY: 727030

African (AFR) AF: 0.000657 AC: 22 AN: 33474

American (AMR) AF: 0.00181 AC: 81 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.00846 AC: 730 AN: 86252

European-Finnish (FIN) AF: 0.000768 AC: 41 AN: 53400

Middle Eastern (MID) AF: 0.0205 AC: 118 AN: 5766

European-Non Finnish (NFE) AF: 0.00519 AC: 5767 AN: 1111672

Other (OTH) AF: 0.00484 AC: 292 AN: 60364

GnomAD4 genome AF: 0.00267 AC: 406 AN: 152180 Hom.: 1 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74390

African (AFR) AF: 0.000867 AC: 36 AN: 41534

American (AMR) AF: 0.00138 AC: 21 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00665 AC: 32 AN: 4814

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10598

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00431 AC: 293 AN: 68008

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00405 Hom.: 7

Bravo AF: 0.00278

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00163 AC: 6

ESP6500EA AF: 0.00427 AC: 35

ExAC AF: 0.00376 AC: 454

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00524

EpiControl AF: 0.00569

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	16
DANN	Benign	0.72
DEOGEN2	Benign	0.00058	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.20	N
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.12
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.015
Sift	Benign	0.77	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.055
MVP		0.25
MPC		0.0055
ClinPred		0.00069	T
GERP RS		0.72
Varity_R		0.022
gMVP		0.21
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs150099163; hg19: chr3-174814909; COSMIC: COSV70794611;