rs387906926

Variant names:

• chr16-5075431-G-A
• rs387906926
• NM_019109.5:c.434G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_019109.5(ALG1):​c.434G>A​(p.Gly145Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALG1 NM_019109.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 5.20
• Publications: 4 publications found

Genes affected

ALG1 (HGNC:18294): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase) The enzyme encoded by this gene catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides. This gene is mutated in congenital disorder of glycosylation type Ik. [provided by RefSeq, Dec 2008]

ALG1 Gene-Disease associations (from GenCC):

• ALG1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_019109.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-5075431-G-A is Pathogenic according to our data. Variant chr16-5075431-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 30537.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019109.5. 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
	ALG1	NM_019109.5	MANE Select	c.434G>A	p.Gly145Asp	missense	Exon 4 of 13	NP_061982.3
	ALG1	NM_001438123.1		c.434G>A	p.Gly145Asp	missense	Exon 4 of 12	NP_001425052.1
	ALG1	NM_001330504.2		c.101G>A	p.Gly34Asp	missense	Exon 4 of 13	NP_001317433.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	ENST00000262374.10	TSL:1 MANE Select	c.434G>A	p.Gly145Asp	missense	Exon 4 of 13	ENSP00000262374.5
	ALG1	ENST00000588623.5	TSL:1	c.101G>A	p.Gly34Asp	missense	Exon 5 of 14	ENSP00000468118.1
	ALG1	ENST00000591822.5	TSL:1	n.*335G>A		non_coding_transcript_exon	Exon 4 of 13	ENSP00000467865.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000725 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	ALG1-congenital disorder of glycosylation (3)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.59	D
PhyloP100		5.2
Sift4G	Benign	0.17	T
MVP		0.88
ClinPred		0.75	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.17
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -33

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

Other links and lift over

dbSNP: rs387906926; hg19: chr16-5125432; COSMIC: COSV99276082; COSMIC: COSV99276082;