11-65046057-C-A

Variant names:

• chr11-65046057-C-A
• rs756376050
• NM_005468.3:c.1913G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005468.3(NAALADL1):​c.1913G>T​(p.Arg638Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. R638H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAALADL1 NM_005468.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 4 publications found

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]

ACMG classification

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=0.16757253).

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.1913G>T	p.Arg638Leu	missense	Exon 16 of 18	NP_005459.2	Q9UQQ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAALADL1	ENST00000358658.8	TSL:1 MANE Select	c.1913G>T	p.Arg638Leu	missense	Exon 16 of 18	ENSP00000351484.3	Q9UQQ1-1
	NAALADL1	ENST00000528884.5	TSL:1	c.-47G>T		5_prime_UTR	Exon 5 of 6	ENSP00000431513.1	E9PKR0
	NAALADL1	ENST00000528977.5	TSL:1	n.2040G>T		non_coding_transcript_exon	Exon 15 of 17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251036 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.64
DANN	Benign	0.87
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-2.0
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.068
Sift	Benign	0.20	T
Sift4G	Uncertain	0.041	D
Polyphen		0.0	B
Vest4		0.23
MutPred		0.67		Loss of catalytic residue at R638 (P = 0.0423)
MVP		0.28
MPC		0.20
ClinPred		0.11	T
GERP RS		-6.8
PromoterAI		0.0046	Neutral
Varity_R		0.20
gMVP		0.36
Mutation Taster		=84/16	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: rs756376050; hg19: chr11-64813529;