Genetic Variant NM_000027.4:c.*220G>C (chr4-177431488-C-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000027.4(AGA):c.*220G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00828 in 597,124 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0073 ( 25 hom., cov: 33)

Exomes 𝑓: 0.0086 ( 77 hom. )

Consequence

AGA
NM_000027.4 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.877

Publications

0 publications found

Variant links:

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, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health

AGA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 4-177431488-C-G is Benign according to our data. Variant chr4-177431488-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 348222.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AGA	NM_000027.4	MANE Select	c.*220G>C	3_prime_UTR	Exon 9 of 9	NP_000018.2	P20933
AGA	NM_001171988.2		c.*220G>C	3_prime_UTR	Exon 9 of 9	NP_001165459.1
AGA	NR_033655.2		n.1247G>C	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.*220G>C		3_prime_UTR	Exon 9 of 9	ENSP00000264595.2	P20933
	AGA	ENST00000926431.1		c.*220G>C		downstream_gene	N/A	ENSP00000596490.1

Frequencies

GnomAD3 genomes

AF:

0.00727

AC:

1105

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0383

Gnomad ASJ

AF:

0.0392

Gnomad EAS

AF:

0.00944

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.0107

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00163

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.0156

AC:

1667

AN:

107080

AF XY:

0.0140

show subpopulations

Gnomad AFR exome

AF:

0.00119

Gnomad AMR exome

AF:

0.0642

Gnomad ASJ exome

AF:

0.0308

Gnomad EAS exome

AF:

0.00715

Gnomad FIN exome

AF:

0.00920

Gnomad NFE exome

AF:

0.00119

Gnomad OTH exome

AF:

0.0138

GnomAD4 exome

AF:

0.00862

AC:

3836

AN:

444964

Hom.:

Cov.:

AF XY:

0.00831

AC XY:

2017

AN XY:

242758

show subpopulations

African (AFR)

AF:

0.00107

AC:

AN:

12122

American (AMR)

AF:

0.0599

AC:

1470

AN:

24550

Ashkenazi Jewish (ASJ)

AF:

0.0340

AC:

532

AN:

15640

East Asian (EAS)

AF:

0.0154

AC:

391

AN:

25446

South Asian (SAS)

AF:

0.00898

AC:

482

AN:

53676

European-Finnish (FIN)

AF:

0.0121

AC:

285

AN:

23546

Middle Eastern (MID)

AF:

0.00147

AC:

AN:

2034

European-Non Finnish (NFE)

AF:

0.00174

AC:

458

AN:

263538

Other (OTH)

AF:

0.00827

AC:

202

AN:

24412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

176

351

527

702

878

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00728

AC:

1107

AN:

152160

Hom.:

Cov.:

AF XY:

0.00848

AC XY:

631

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41518

American (AMR)

AF:

0.0384

AC:

586

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0392

AC:

136

AN:

3472

East Asian (EAS)

AF:

0.00946

AC:

AN:

5178

South Asian (SAS)

AF:

0.00705

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0107

AC:

113

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00163

AC:

111

AN:

67996

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00773

Hom.:

Bravo

AF:

0.00976

Asia WGS

AF:

0.0210

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aspartylglucosaminuria (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.61

(source)

DANN

Benign

0.46

PhyloP100

-0.88

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over