11-65045284-A-G

Variant names:

• chr11-65045284-A-G
• NM_005468.3:c.2210T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005468.3(NAALADL1):​c.2210T>C​(p.Val737Ala) 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. 14/21 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NAALADL1 NM_005468.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23868963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAALADL1	NM_005468.3	c.2210T>C	p.Val737Ala	missense_variant	Exon 18 of 18	ENST00000358658.8	NP_005459.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAALADL1	ENST00000358658.8	c.2210T>C	p.Val737Ala	missense_variant	Exon 18 of 18	1	NM_005468.3	ENSP00000351484.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453920 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721986

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2210T>C (p.V737A) alteration is located in exon 18 (coding exon 18) of the NAALADL1 gene. This alteration results from a T to C substitution at nucleotide position 2210, causing the valine (V) at amino acid position 737 to be replaced by an alanine (A). 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	0.096
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T;.;.;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.57	T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.059	T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.17	B;.;.;.;.
Vest4		0.19
MutPred		0.77		Loss of helix (P = 0.028);.;.;.;.;
MVP		0.45
MPC		0.21
ClinPred		0.43	T
GERP RS		3.4
Varity_R		0.47
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64812756;