rs114918706

chr4-177442316-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000027.4(AGA):c.60A>G(p.Leu20=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000944 in 1,614,058 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L20L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0042 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (1 hom.)
• Consequence: AGA NM_000027.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.41

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 4-177442316-T-C is Benign according to our data. Variant chr4-177442316-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 348238.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.41 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00418 (637/152284) while in subpopulation AFR AF= 0.0141 (588/41568). AF 95% confidence interval is 0.0132. There are 7 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGA	NM_000027.4	c.60A>G	p.Leu20=	synonymous_variant	1/9	ENST00000264595.7
AGA	NM_001171988.2	c.60A>G	p.Leu20=	synonymous_variant	1/9
AGA	XM_047449722.1	c.60A>G	p.Leu20=	synonymous_variant	1/7
AGA	NR_033655.2	n.122A>G		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGA	ENST00000264595.7	c.60A>G	p.Leu20=	synonymous_variant	1/9	1	NM_000027.4	P1
AGA	ENST00000506853.5	n.94A>G		non_coding_transcript_exon_variant	1/6	2
AGA	ENST00000510955.5	n.94A>G		non_coding_transcript_exon_variant	1/4	2
AGA	ENST00000511231.1	n.94A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00417 AC: 634 AN: 152166 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00141 AC: 354 AN: 251146 Hom.: 2 AF XY: 0.00114 AC XY: 155 AN XY: 135862

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000980

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000606 AC: 886 AN: 1461774 Hom.: 1 Cov.: 34 AF XY: 0.000532 AC XY: 387 AN XY: 727200

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000579

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00418 AC: 637 AN: 152284 Hom.: 7 Cov.: 32 AF XY: 0.00406 AC XY: 302 AN XY: 74454

Gnomad4 AFR AF: 0.0141

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00216 Hom.: 3

Bravo AF: 0.00508

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aspartylglucosaminuria Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.87
Dann	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs114918706; hg19: chr4-178363470;