rs889118173

chr3-184242638-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005787.6(ALG3):c.1193C>T(p.Thr398Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,417,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: ALG3 NM_005787.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.11

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG3	NM_005787.6	c.1193C>T	p.Thr398Ile	missense_variant	9/9	ENST00000397676.8
ALG3	NM_001006941.2	c.1049C>T	p.Thr350Ile	missense_variant	9/9
ALG3	NR_024533.1	n.1124C>T		non_coding_transcript_exon_variant	8/8
ALG3	NR_024534.1	n.1187C>T		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG3	ENST00000397676.8	c.1193C>T	p.Thr398Ile	missense_variant	9/9	1	NM_005787.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000464 AC: 1 AN: 215460 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 115074

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000360 AC: 51 AN: 1417950 Hom.: 0 Cov.: 32 AF XY: 0.0000300 AC XY: 21 AN XY: 699060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000469

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Dec 28, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.86
Sift	Benign	0.033	D;T;T
Sift4G	Uncertain	0.034	D;T;T
Polyphen		1.0	D;.;D
Vest4		0.90
MutPred		0.56		Gain of catalytic residue at T398 (P = 0.0145);.;.;
MVP		0.99
MPC		0.48
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs889118173; hg19: chr3-183960426;