NM_000642.3:c.1284-4A>G

Variant names:

• chr1-99876454-A-G
• rs372612377
• NM_000642.3:c.1284-4A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000642.3(AGL):​c.1284-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,568,282 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000066 (1 hom.)
• Consequence: AGL NM_000642.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002757
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.30
• Publications: 0 publications found

Genes affected

AGL (HGNC:321): (amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase) This gene encodes the glycogen debrancher enzyme which is involved in glycogen degradation. This enzyme has two independent catalytic activities which occur at different sites on the protein: a 4-alpha-glucotransferase activity and a amylo-1,6-glucosidase activity. Mutations in this gene are associated with glycogen storage disease although a wide range of enzymatic and clinical variability occurs which may be due to tissue-specific alternative splicing. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

AGL Gene-Disease associations (from GenCC):

• glycogen storage disease III

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-99876454-A-G is Benign according to our data. Variant chr1-99876454-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 456453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000657 (93/1416112) while in subpopulation EAS AF = 0.0012 (46/38392). AF 95% confidence interval is 0.000923. There are 1 homozygotes in GnomAdExome4. There are 36 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000642.3. 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
	AGL	NM_000642.3	MANE Select	c.1284-4A>G		splice_region intron	N/A	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.1284-4A>G		splice_region intron	N/A	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.1284-4A>G		splice_region intron	N/A	NP_000634.2	A0A0S2A4E4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.1284-4A>G		splice_region intron	N/A	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.1284-4A>G		splice_region intron	N/A	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.1284-4A>G		splice_region intron	N/A	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000154 AC: 35 AN: 227604 AF XY: 0.000121

Gnomad AFR exome AF: 0.000145

Gnomad AMR exome AF: 0.0000905

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00181

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000657 AC: 93 AN: 1416112 Hom.: 1 Cov.: 27 AF XY: 0.0000510 AC XY: 36 AN XY: 705434

African (AFR) AF: 0.0000313 AC: 1 AN: 31902

American (AMR) AF: 0.0000920 AC: 4 AN: 43470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25670

East Asian (EAS) AF: 0.00120 AC: 46 AN: 38392

South Asian (SAS) AF: 0.00 AC: 0 AN: 83568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1076156

Other (OTH) AF: 0.000682 AC: 40 AN: 58630

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74324

African (AFR) AF: 0.000193 AC: 8 AN: 41456

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

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

East Asian (EAS) AF: 0.000961 AC: 5 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000178

Asia WGS AF: 0.00433 AC: 15 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Glycogen storage disease type III (2)
-	-	2	not provided (2)
-	-	1	AGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.38
DANN	Benign	0.56
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.0060
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

Other links and lift over

dbSNP: rs372612377; hg19: chr1-100342010;