rs267606651

Variant names:

• chr16-5081009-A-C
• rs267606651
• NM_019109.5:c.1025A>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_019109.5(ALG1):​c.1025A>C​(p.Gln342Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000426 in 1,433,072 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: ALG1 NM_019109.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.46
• Publications: 3 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: Pathogenic. The variant received 16 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 16-5081009-A-C is Pathogenic according to our data. Variant chr16-5081009-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	NM_019109.5	MANE Select	c.1025A>C	p.Gln342Pro	missense	Exon 10 of 13	NP_061982.3
	ALG1	NM_001438123.1		c.986A>C	p.Gln329Pro	missense	Exon 9 of 12	NP_001425052.1
	ALG1	NM_001330504.2		c.692A>C	p.Gln231Pro	missense	Exon 10 of 13	NP_001317433.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	ENST00000262374.10	TSL:1 MANE Select	c.1025A>C	p.Gln342Pro	missense	Exon 10 of 13	ENSP00000262374.5
	ALG1	ENST00000588623.5	TSL:1	c.692A>C	p.Gln231Pro	missense	Exon 11 of 14	ENSP00000468118.1
	ALG1	ENST00000591822.5	TSL:1	n.*926A>C		non_coding_transcript_exon	Exon 10 of 13	ENSP00000467865.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000428 AC: 1 AN: 233530 AF XY: 0.00000779

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000921

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000426 AC: 61 AN: 1433072 Hom.: 0 Cov.: 33 AF XY: 0.0000379 AC XY: 27 AN XY: 713104

African (AFR) AF: 0.00 AC: 0 AN: 33116

American (AMR) AF: 0.00 AC: 0 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 39056

South Asian (SAS) AF: 0.00 AC: 0 AN: 86056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4068

European-Non Finnish (NFE) AF: 0.0000543 AC: 60 AN: 1104308

Other (OTH) AF: 0.0000169 AC: 1 AN: 59294

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000866 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	ALG1-congenital disorder of glycosylation (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.5
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.42
Sift	Benign	0.10	T
Sift4G	Benign	0.28	T
Polyphen		0.020	B
Vest4		0.77
MutPred		0.83		Loss of sheet (P = 0.0817)
MVP		0.80
MPC		0.054
ClinPred		0.36	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.94
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267606651; hg19: chr16-5131010;