NM_019109.5:c.1A>G

Variant names:

• chr16-5071850-A-G
• rs1332958042
• NM_019109.5:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_019109.5(ALG1):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000344 in 1,451,892 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: 0.0000034 (0 hom.)
• Consequence: ALG1 NM_019109.5 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.02
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, PanelApp Australia, G2P, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 10 pathogenic variants. Next in-frame start position is after 49 codons. Genomic position: 5071994. Lost 0.104 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-5071850-A-G is Pathogenic according to our data. Variant chr16-5071850-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3580756.Status of the report is criteria_provided_single_submitter, 1 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.1A>G	p.Met1?	start_lost	Exon 1 of 13	NP_061982.3
	ALG1	NM_001438123.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 12	NP_001425052.1	A0A804HJL6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	ENST00000262374.10	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 13	ENSP00000262374.5	Q9BT22-1
	ALG1	ENST00000588623.5	TSL:1	c.-125-1101A>G		intron	N/A	ENSP00000468118.1	Q9BT22-2
	ALG1	ENST00000591822.5	TSL:1	n.1A>G		non_coding_transcript_exon	Exon 1 of 13	ENSP00000467865.1	K7EQK1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000428 AC: 1 AN: 233484 AF XY: 0.00000780

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1451892 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722592

African (AFR) AF: 0.0000299 AC: 1 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5220

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111064

Other (OTH) AF: 0.00 AC: 0 AN: 60120

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	ALG1-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.60	T
PhyloP100		5.0
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.39
Sift	Benign	0.040	D
Sift4G	Benign	0.15	T
Polyphen		0.012	B
Vest4		0.84
MutPred		0.91		Loss of helix (P = 0.1299)
MVP		0.78
ClinPred		0.99	D
GERP RS		4.8
PromoterAI		-0.91	Under-expression
Varity_R		0.67
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -1

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

Other links and lift over

dbSNP: rs1332958042; hg19: chr16-5121851;