rs56849061

Variant names:

• chr4-177431784-G-A
• rs56849061
• NM_000027.4:c.965C>T
• AGA p.Thr322Ile

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000027.4(AGA):​c.965C>T​(p.Thr322Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,613,836 control chromosomes in the GnomAD database, including 10 homozygotes. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T322T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (5 hom.)
• Consequence: AGA NM_000027.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.06
• Publications: 2 publications found

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]

AGA Gene-Disease associations (from GenCC):

• aspartylglucosaminuria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women's Health, G2P, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009900689).
• BP6: Variant 4-177431784-G-A is Benign according to our data. Variant chr4-177431784-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 387711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00383 (583/152258) while in subpopulation AFR AF = 0.0134 (557/41546). AF 95% confidence interval is 0.0125. There are 5 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000027.4. 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
	AGA	NM_000027.4	MANE Select	c.965C>T	p.Thr322Ile	missense	Exon 9 of 9	NP_000018.2	P20933
	AGA	NM_001171988.2		c.935C>T	p.Thr312Ile	missense	Exon 9 of 9	NP_001165459.1
	AGA	NR_033655.2		n.951C>T		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGA	ENST00000264595.7	TSL:1 MANE Select	c.965C>T	p.Thr322Ile	missense	Exon 9 of 9	ENSP00000264595.2	P20933
	AGA	ENST00000926431.1		c.980C>T	p.Thr327Ile	missense	Exon 9 of 9	ENSP00000596490.1

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 579 AN: 152140 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000845 AC: 212 AN: 250952 AF XY: 0.000693

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000322 AC: 470 AN: 1461578 Hom.: 5 Cov.: 31 AF XY: 0.000281 AC XY: 204 AN XY: 727086

African (AFR) AF: 0.0115 AC: 386 AN: 33470

American (AMR) AF: 0.000514 AC: 23 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39658

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111808

Other (OTH) AF: 0.000778 AC: 47 AN: 60384

GnomAD4 genome AF: 0.00383 AC: 583 AN: 152258 Hom.: 5 Cov.: 33 AF XY: 0.00377 AC XY: 281 AN XY: 74452

African (AFR) AF: 0.0134 AC: 557 AN: 41546

American (AMR) AF: 0.00137 AC: 21 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00138 Hom.: 3

Bravo AF: 0.00426

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Aspartylglucosaminuria (4)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0094
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.22
Sift	Benign	0.18	T
Sift4G	Benign	0.21	T
Varity_R		0.18
gMVP		0.83
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56849061;

hg19: chr4-178352938;