rs74626221

chr4-177442342-C-Achr4-177442342-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000027.4(AGA):c.34G>T(p.Val12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,614,112 control chromosomes in the GnomAD database, including 415 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.015 (27 hom., cov: 32)
  • Exomes 𝑓: 0.021 (388 hom.)
• Consequence: AGA NM_000027.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.74

Genes affected

AGA (HGNC:318): (aspartylglucosaminidase) This gene encodes a member of the N-terminal nucleophile (Ntn) hydrolase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta chains that comprise the mature enzyme. This enzyme is involved in the catabolism of N-linked oligosaccharides of glycoproteins. It cleaves asparagine from N-acetylglucosamines as one of the final steps in the lysosomal breakdown of glycoproteins. Mutations in this gene are associated with the lysosomal storage disease aspartylglycosaminuria that results in progressive neurodegeneration. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is subject to proteolytic processing. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030047).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.015 (2282/152348) while in subpopulation NFE AF= 0.0232 (1580/68028). AF 95% confidence interval is 0.0223. There are 27 homozygotes in gnomad4. There are 1030 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGA	NM_000027.4	c.34G>T	p.Val12Leu	missense_variant	1/9	ENST00000264595.7
AGA	NM_001171988.2	c.34G>T	p.Val12Leu	missense_variant	1/9
AGA	XM_047449722.1	c.34G>T	p.Val12Leu	missense_variant	1/7
AGA	NR_033655.2	n.96G>T		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGA	ENST00000264595.7	c.34G>T	p.Val12Leu	missense_variant	1/9	1	NM_000027.4	P1
AGA	ENST00000506853.5	n.68G>T		non_coding_transcript_exon_variant	1/6	2
AGA	ENST00000510955.5	n.68G>T		non_coding_transcript_exon_variant	1/4	2
AGA	ENST00000511231.1	n.68G>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2283 AN: 152230 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0144 AC: 3609 AN: 251166 Hom.: 48 AF XY: 0.0145 AC XY: 1971 AN XY: 135860

Gnomad AFR exome AF: 0.00481

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00402

Gnomad FIN exome AF: 0.00481

Gnomad NFE exome AF: 0.0225

Gnomad OTH exome AF: 0.0223

GnomAD4 exome AF: 0.0208 AC: 30384 AN: 1461764 Hom.: 388 Cov.: 34 AF XY: 0.0205 AC XY: 14883 AN XY: 727194

Gnomad4 AFR exome AF: 0.00370

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0209

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00428

Gnomad4 FIN exome AF: 0.00537

Gnomad4 NFE exome AF: 0.0244

Gnomad4 OTH exome AF: 0.0202

GnomAD4 genome AF: 0.0150 AC: 2282 AN: 152348 Hom.: 27 Cov.: 32 AF XY: 0.0138 AC XY: 1030 AN XY: 74498

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.0177

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0206 Hom.: 49

Bravo AF: 0.0158

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0260 AC: 224

ExAC AF: 0.0144 AC: 1753

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0274

EpiControl AF: 0.0247

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aspartylglucosaminuria Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Sep 19, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 02, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	This variant is associated with the following publications: (PMID: 11309371) -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.20
Dann	Benign	0.65
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.71	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.23
Sift	Benign	0.70	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.068
MutPred		0.79		Loss of sheet (P = 0.0011);
MPC		0.11
ClinPred		0.0061	T
GERP RS		-7.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.040
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs74626221; hg19: chr4-178363496; COSMIC: COSV52806729; COSMIC: COSV52806729;