rs79144888

chr3-184242560-G-Achr3-184242560-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005787.6(ALG3):c.1271C>T(p.Pro424Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000644 in 1,610,696 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P424P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00091 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (11 hom.)
• Consequence: ALG3 NM_005787.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.17

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005445808).
• BP6: Variant 3-184242560-G-A is Benign according to our data. Variant chr3-184242560-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 166676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000906 (138/152336) while in subpopulation EAS AF= 0.0216 (112/5180). AF 95% confidence interval is 0.0184. There are 2 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG3	NM_005787.6	c.1271C>T	p.Pro424Leu	missense_variant	9/9	ENST00000397676.8
ALG3	NM_001006941.2	c.1127C>T	p.Pro376Leu	missense_variant	9/9
ALG3	NR_024533.1	n.1202C>T		non_coding_transcript_exon_variant	8/8
ALG3	NR_024534.1	n.1265C>T		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG3	ENST00000397676.8	c.1271C>T	p.Pro424Leu	missense_variant	9/9	1	NM_005787.6	P1

Frequencies

GnomAD3 genomes AF: 0.000913 AC: 139 AN: 152218 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0218

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00178 AC: 436 AN: 245560 Hom.: 5 AF XY: 0.00168 AC XY: 224 AN XY: 133446

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.000611

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0208

Gnomad SAS exome AF: 0.00119

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000616 AC: 899 AN: 1458360 Hom.: 11 Cov.: 32 AF XY: 0.000664 AC XY: 481 AN XY: 724788

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000583

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0169

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000780

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152336 Hom.: 2 Cov.: 33 AF XY: 0.00118 AC XY: 88 AN XY: 74484

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0216

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.00124

ExAC AF: 0.00164 AC: 199

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 03, 2014	- -

ALG3-congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	21
Dann	Benign	0.88
DEOGEN2	Benign	0.084	T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.0054	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.78	N;N;N
REVEL	Benign	0.25
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.17
MVP		0.88
MPC		0.086
ClinPred		0.0094	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs79144888; hg19: chr3-183960348; COSMIC: COSV99891876; COSMIC: COSV99891876;