16-5073200-A-C

Variant names:

• chr16-5073200-A-C
• rs113219939
• NM_019109.5:c.334A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019109.5(ALG1):​c.334A>C​(p.Met112Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,614,118 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M112T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (36 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (38 hom.)
• Consequence: ALG1 NM_019109.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.133
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029365122).
• BP6: Variant 16-5073200-A-C is Benign according to our data. Variant chr16-5073200-A-C is described in ClinVar as Benign. ClinVar VariationId is 384254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1773/152224) while in subpopulation AFR AF = 0.0401 (1667/41540). AF 95% confidence interval is 0.0385. There are 36 homozygotes in GnomAd4. There are 850 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

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.334A>C	p.Met112Leu	missense	Exon 3 of 13	NP_061982.3
	ALG1	NM_001438123.1		c.334A>C	p.Met112Leu	missense	Exon 3 of 12	NP_001425052.1	A0A804HJL6
	ALG1	NM_001330504.2		c.1A>C	p.Met1?	initiator_codon	Exon 3 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.334A>C	p.Met112Leu	missense	Exon 3 of 13	ENSP00000262374.5	Q9BT22-1
	ALG1	ENST00000588623.5	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 4 of 14	ENSP00000468118.1	Q9BT22-2
	ALG1	ENST00000591822.5	TSL:1	n.*235A>C		non_coding_transcript_exon	Exon 3 of 13	ENSP00000467865.1	K7EQK1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1763 AN: 152106 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00815

GnomAD2 exomes AF: 0.00315 AC: 792 AN: 251490 AF XY: 0.00240

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00136 AC: 1986 AN: 1461894 Hom.: 38 Cov.: 32 AF XY: 0.00121 AC XY: 881 AN XY: 727248

African (AFR) AF: 0.0430 AC: 1439 AN: 33480

American (AMR) AF: 0.00277 AC: 124 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.000174 AC: 193 AN: 1112012

Other (OTH) AF: 0.00334 AC: 202 AN: 60396

GnomAD4 genome AF: 0.0116 AC: 1773 AN: 152224 Hom.: 36 Cov.: 33 AF XY: 0.0114 AC XY: 850 AN XY: 74408

African (AFR) AF: 0.0401 AC: 1667 AN: 41540

American (AMR) AF: 0.00412 AC: 63 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68008

Other (OTH) AF: 0.00806 AC: 17 AN: 2108

Alfa AF: 0.00213 Hom.: 7

Bravo AF: 0.0134

ESP6500AA AF: 0.0385 AC: 169

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00395 AC: 480

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.4
DANN	Benign	0.71
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.13
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.50		Loss of MoRF binding (P = 0.0852)
MVP		0.52
MPC		0.038
ClinPred		0.0048	T
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.46
Mutation Taster		=149/51	polymorphism

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: rs113219939; hg19: chr16-5123201;