3-184243878-G-A

Variant names:

• chr3-184243878-G-A
• rs2233466
• NM_005787.6:c.845C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_005787.6(ALG3):​c.845C>T​(p.Ala282Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,614,008 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A282A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: ALG3 NM_005787.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.56
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.31675 (below the threshold of 3.09). Trascript score misZ: 0.74965 (below the threshold of 3.09). GenCC associations: The gene is linked to ALG3-congenital disorder of glycosylation.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0148973465).
• BP6: Variant 3-184243878-G-A is Benign according to our data. Variant chr3-184243878-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 344352.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000919 (140/152352) while in subpopulation AFR AF = 0.00279 (116/41582). AF 95% confidence interval is 0.00238. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG3	NM_005787.6	MANE Select	c.845C>T	p.Ala282Val	missense	Exon 6 of 9	NP_005778.1	Q92685-1
	ALG3	NM_001006941.2		c.701C>T	p.Ala234Val	missense	Exon 6 of 9	NP_001006942.1	Q92685-2
	ALG3	NR_024533.1		n.776C>T		non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG3	ENST00000397676.8	TSL:1 MANE Select	c.845C>T	p.Ala282Val	missense	Exon 6 of 9	ENSP00000380793.3	Q92685-1
	ALG3	ENST00000445626.6	TSL:1	c.701C>T	p.Ala234Val	missense	Exon 6 of 9	ENSP00000402744.2	Q92685-2
	ALG3	ENST00000411922.5	TSL:1	n.*421C>T		non_coding_transcript_exon	Exon 5 of 8	ENSP00000394917.1	F8WE30

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000503 AC: 125 AN: 248602 AF XY: 0.000407

Gnomad AFR exome AF: 0.00260

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00488

Gnomad EAS exome AF: 0.00128

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000248 AC: 363 AN: 1461656 Hom.: 1 Cov.: 31 AF XY: 0.000228 AC XY: 166 AN XY: 727114

African (AFR) AF: 0.00281 AC: 94 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00528 AC: 138 AN: 26134

East Asian (EAS) AF: 0.00154 AC: 61 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111854

Other (OTH) AF: 0.000580 AC: 35 AN: 60374

GnomAD4 genome AF: 0.000919 AC: 140 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74506

African (AFR) AF: 0.00279 AC: 116 AN: 41582

American (AMR) AF: 0.000327 AC: 5 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000548 Hom.: 0

Bravo AF: 0.00109

ESP6500AA AF: 0.00221 AC: 9

ESP6500EA AF: 0.000358 AC: 3

ExAC AF: 0.000471 AC: 57

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	ALG3-congenital disorder of glycosylation (2)
-	-	1	ALG3-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.031
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.6
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.26
Sift	Benign	0.29	T
Sift4G	Benign	0.062	T
Polyphen		0.16	B
Vest4		0.17
MVP		0.95
MPC		0.10
ClinPred		0.0089	T
GERP RS		4.7
Varity_R		0.072
gMVP		0.39
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2233466; hg19: chr3-183961666; COSMIC: COSV56610767; COSMIC: COSV56610767;