16-5078856-G-C

Variant names:

• chr16-5078856-G-C
• rs12921879
• NM_019109.5:c.840G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_019109.5(ALG1):​c.840G>C​(p.Leu280Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0499 in 1,611,694 control chromosomes in the GnomAD database, including 2,297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L280L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.047 (218 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2079 hom.)
• Consequence: ALG1 NM_019109.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.802
• Publications: 6 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: G2P, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 16-5078856-G-C is Benign according to our data. Variant chr16-5078856-G-C is described in ClinVar as Benign. ClinVar VariationId is 95937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.802 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

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.840G>C	p.Leu280Leu	synonymous	Exon 7 of 13	NP_061982.3
	ALG1	NM_001438123.1		c.840G>C	p.Leu280Leu	synonymous	Exon 7 of 12	NP_001425052.1	A0A804HJL6
	ALG1	NM_001330504.2		c.507G>C	p.Leu169Leu	synonymous	Exon 7 of 13	NP_001317433.1	Q9BT22-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	ENST00000262374.10	TSL:1 MANE Select	c.840G>C	p.Leu280Leu	synonymous	Exon 7 of 13	ENSP00000262374.5	Q9BT22-1
	ALG1	ENST00000588623.5	TSL:1	c.507G>C	p.Leu169Leu	synonymous	Exon 8 of 14	ENSP00000468118.1	Q9BT22-2
	ALG1	ENST00000591822.5	TSL:1	n.*741G>C		non_coding_transcript_exon	Exon 7 of 13	ENSP00000467865.1	K7EQK1

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 7155 AN: 152190 Hom.: 218 Cov.: 33

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0441

Gnomad ASJ AF: 0.0738

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0541

Gnomad OTH AF: 0.0559

GnomAD2 exomes AF: 0.0388 AC: 9626 AN: 248140 AF XY: 0.0385

Gnomad AFR exome AF: 0.0513

Gnomad AMR exome AF: 0.0352

Gnomad ASJ exome AF: 0.0676

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0205

Gnomad NFE exome AF: 0.0529

Gnomad OTH exome AF: 0.0509

GnomAD4 exome AF: 0.0502 AC: 73191 AN: 1459386 Hom.: 2079 Cov.: 62 AF XY: 0.0487 AC XY: 35370 AN XY: 726032

African (AFR) AF: 0.0509 AC: 1702 AN: 33406

American (AMR) AF: 0.0358 AC: 1598 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 1782 AN: 26098

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0100 AC: 863 AN: 86144

European-Finnish (FIN) AF: 0.0205 AC: 1090 AN: 53174

Middle Eastern (MID) AF: 0.0887 AC: 378 AN: 4260

European-Non Finnish (NFE) AF: 0.0562 AC: 62498 AN: 1111714

Other (OTH) AF: 0.0544 AC: 3277 AN: 60202

GnomAD4 genome AF: 0.0470 AC: 7162 AN: 152308 Hom.: 218 Cov.: 33 AF XY: 0.0441 AC XY: 3284 AN XY: 74474

African (AFR) AF: 0.0518 AC: 2155 AN: 41578

American (AMR) AF: 0.0441 AC: 674 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0738 AC: 256 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4830

European-Finnish (FIN) AF: 0.0188 AC: 200 AN: 10620

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0541 AC: 3681 AN: 68026

Other (OTH) AF: 0.0553 AC: 117 AN: 2114

Alfa AF: 0.0432 Hom.: 61

Bravo AF: 0.0490

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.0594

EpiControl AF: 0.0602

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.3
DANN	Benign	0.75
PhyloP100		0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	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: rs12921879; hg19: chr16-5128857;