rs2233465

Variant names:

• chr3-184244046-A-G
• rs2233465
• NM_005787.6:c.727-50T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005787.6(ALG3):​c.727-50T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0335 in 1,562,822 control chromosomes in the GnomAD database, including 1,018 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (74 hom., cov: 32)
  • Exomes 𝑓: 0.034 (944 hom.)
• Consequence: ALG3 NM_005787.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.144
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-184244046-A-G is Benign according to our data. Variant chr3-184244046-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0263 (4004/152274) while in subpopulation NFE AF = 0.0411 (2792/68000). AF 95% confidence interval is 0.0398. There are 74 homozygotes in GnomAd4. There are 1826 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 74 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG3	NM_005787.6	MANE Select	c.727-50T>C		intron	N/A	NP_005778.1
	ALG3	NM_001006941.2		c.583-50T>C		intron	N/A	NP_001006942.1
	ALG3	NR_024533.1		n.658-50T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG3	ENST00000397676.8	TSL:1 MANE Select	c.727-50T>C		intron	N/A	ENSP00000380793.3
	ALG3	ENST00000445626.6	TSL:1	c.583-50T>C		intron	N/A	ENSP00000402744.2
	ALG3	ENST00000411922.5	TSL:1	n.*303-50T>C		intron	N/A	ENSP00000394917.1

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 4003 AN: 152156 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0280

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0410

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0264 AC: 6106 AN: 231000 AF XY: 0.0267

Gnomad AFR exome AF: 0.00564

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0483

Gnomad EAS exome AF: 0.0000564

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0369

GnomAD4 exome AF: 0.0343 AC: 48360 AN: 1410548 Hom.: 944 Cov.: 25 AF XY: 0.0336 AC XY: 23491 AN XY: 699694

African (AFR) AF: 0.00557 AC: 181 AN: 32488

American (AMR) AF: 0.0203 AC: 885 AN: 43552

Ashkenazi Jewish (ASJ) AF: 0.0456 AC: 1120 AN: 24562

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39154

South Asian (SAS) AF: 0.00601 AC: 496 AN: 82506

European-Finnish (FIN) AF: 0.0228 AC: 1188 AN: 52166

Middle Eastern (MID) AF: 0.0439 AC: 180 AN: 4102

European-Non Finnish (NFE) AF: 0.0395 AC: 42403 AN: 1073754

Other (OTH) AF: 0.0327 AC: 1906 AN: 58264

GnomAD4 genome AF: 0.0263 AC: 4004 AN: 152274 Hom.: 74 Cov.: 32 AF XY: 0.0245 AC XY: 1826 AN XY: 74460

African (AFR) AF: 0.00642 AC: 267 AN: 41568

American (AMR) AF: 0.0280 AC: 428 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4824

European-Finnish (FIN) AF: 0.0217 AC: 231 AN: 10622

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0411 AC: 2792 AN: 68000

Other (OTH) AF: 0.0327 AC: 69 AN: 2112

Alfa AF: 0.0361 Hom.: 34

Bravo AF: 0.0260

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.40
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2233465; hg19: chr3-183961834;