3-184248747-G-T

Variant names:

• chr3-184248747-G-T
• rs1336047164
• NM_005787.6:c.194C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_005787.6(ALG3):​c.194C>A​(p.Ala65Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,276 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A65V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: ALG3 NM_005787.6 missense, splice_region
• Scores: Splicing: ADA: 0.9918
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.23
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen, PanelApp Australia, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG3	NM_005787.6	c.194C>A	p.Ala65Glu	missense_variant, splice_region_variant	Exon 1 of 9	ENST00000397676.8	NP_005778.1
ALG3	NR_024533.1	n.225C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 8
ALG3	NM_001006941.2	c.52+479C>A		intron_variant	Intron 1 of 8		NP_001006942.1
ALG3	NR_024534.1	n.190+35C>A		intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG3	ENST00000397676.8	c.194C>A	p.Ala65Glu	missense_variant, splice_region_variant	Exon 1 of 9	1	NM_005787.6	ENSP00000380793.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098276 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 542806

African (AFR) AF: 0.00 AC: 0 AN: 24066

American (AMR) AF: 0.00 AC: 0 AN: 32280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16356

East Asian (EAS) AF: 0.00 AC: 0 AN: 22764

South Asian (SAS) AF: 0.00 AC: 0 AN: 77778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3932

European-Non Finnish (NFE) AF: 0.00000118 AC: 1 AN: 845972

Other (OTH) AF: 0.00 AC: 0 AN: 40992

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Benign	1.9	L
PhyloP100		8.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.13	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.018	D
Sift4G	Benign	0.10	T
Polyphen		0.015	B
Vest4		0.66
MutPred		0.54		Loss of catalytic residue at Y66 (P = 0.1017);
MVP		0.95
MPC		0.14
ClinPred		0.93	D
GERP RS		5.4
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.71
gMVP		0.90
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.95
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: rs1336047164; hg19: chr3-183966535;