dbSNP rs387906273: ALG3:p.Gly55Gly (chr3-184248776-G-A) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3PM2PP3_ModeratePP5_Very_Strong

The NM_005787.6(ALG3):c.165C>T(p.Gly55Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,359,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003922108: RT-PCR analysis of RNA from affected tissue showed altered splicing of exon 1, leading to a 35bp deletion (c.160_196del), frameshift, and premature truncation (PMID:15108280)." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

ALG3
NM_005787.6 synonymous

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.777

Publications

8 publications found

Variant links:

Genes affected

ALG3 (HGNC:23056): (ALG3 alpha-1,3- mannosyltransferase) This gene encodes a member of the ALG3 family. The encoded protein catalyses the addition of the first dol-P-Man derived mannose in an alpha 1,3 linkage to Man5GlcNAc2-PP-Dol. Defects in this gene have been associated with congenital disorder of glycosylation type Id (CDG-Id) characterized by abnormal N-glycosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

ALG3 Gene-Disease associations (from GenCC):

ALG3-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ALG3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV003922108: RT-PCR analysis of RNA from affected tissue showed altered splicing of exon 1, leading to a 35bp deletion (c.160_196del), frameshift, and premature truncation (PMID: 15108280).; SCV005079953: This variant is demonstrated to cause aberrant splicing and result in loss of function (Denecke et al., 2004); PMID: 30487145, 31618474, 27172925, 31067009, 15108280, 32389449

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 3-184248776-G-A is Pathogenic according to our data. Variant chr3-184248776-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005787.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG3	NM_005787.6	MANE Select	c.165C>T	p.Gly55Gly	synonymous	Exon 1 of 9	NP_005778.1	Q92685-1
ALG3	NM_001006941.2		c.52+450C>T		intron	N/A	NP_001006942.1	Q92685-2
ALG3	NR_024533.1		n.196C>T		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG3	ENST00000397676.8	TSL:1 MANE Select	c.165C>T	p.Gly55Gly	synonymous	Exon 1 of 9	ENSP00000380793.3	Q92685-1
ALG3	ENST00000445626.6	TSL:1	c.52+450C>T		intron	N/A	ENSP00000402744.2	Q92685-2
ALG3	ENST00000411922.5	TSL:1	n.165C>T		non_coding_transcript_exon	Exon 1 of 8	ENSP00000394917.1	F8WE30

Frequencies

GnomAD3 genomes

AF:

0.0000138

AC:

AN:

144924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000304

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000425

AC:

AN:

235522

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000964

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000519

AC:

AN:

1214886

Hom.:

Cov.:

AF XY:

0.0000567

AC XY:

AN XY:

599386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26174

American (AMR)

AF:

0.00

AC:

AN:

36586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17132

East Asian (EAS)

AF:

0.00

AC:

AN:

18198

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83508

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4198

European-Non Finnish (NFE)

AF:

0.0000629

AC:

AN:

953352

Other (OTH)

AF:

0.0000456

AC:

AN:

43888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000138

AC:

AN:

144924

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70600

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40154

American (AMR)

AF:

0.00

AC:

AN:

14604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3380

East Asian (EAS)

AF:

0.00

AC:

AN:

4318

South Asian (SAS)

AF:

0.00

AC:

AN:

4068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000304

AC:

AN:

65800

Other (OTH)

AF:

0.00

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000632

Hom.:

Bravo

AF:

0.0000227

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

ALG3-congenital disorder of glycosylation (4)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

PhyloP100

0.78

PromoterAI

0.034

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.85

Position offset: -31

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over