16-5078856-G-C

Position:

• chr16-5078856-G-C

Variant summary

Our verdict is Benign. Variant got -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 (★★).

• 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG1	NM_019109.5	c.840G>C	p.Leu280Leu	synonymous_variant	7/13	ENST00000262374.10	NP_061982.3
ALG1	NM_001330504.2	c.507G>C	p.Leu169Leu	synonymous_variant	7/13		NP_001317433.1
ALG1	XM_017023457.3	c.840G>C	p.Leu280Leu	synonymous_variant	7/12		XP_016878946.1
ALG1	XR_007064892.1	n.847G>C		non_coding_transcript_exon_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10	c.840G>C	p.Leu280Leu	synonymous_variant	7/13	1	NM_019109.5	ENSP00000262374.5

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

GnomAD3 exomes AF: 0.0388 AC: 9626 AN: 248140 Hom.: 261 AF XY: 0.0385 AC XY: 5185 AN XY: 134782

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 SAS exome AF: 0.00935

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

Gnomad4 AFR exome AF: 0.0509

Gnomad4 AMR exome AF: 0.0358

Gnomad4 ASJ exome AF: 0.0683

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0100

Gnomad4 FIN exome AF: 0.0205

Gnomad4 NFE exome AF: 0.0562

Gnomad4 OTH exome AF: 0.0544

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

Gnomad4 AFR AF: 0.0518

Gnomad4 AMR AF: 0.0441

Gnomad4 ASJ AF: 0.0738

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.0188

Gnomad4 NFE AF: 0.0541

Gnomad4 OTH AF: 0.0553

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

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2016	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. -

ALG1-congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

ALG1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.3
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs12921879; hg19: chr16-5128857;