rs145474820

Positions:

• chr16-5072040-C-A
• chr16-5072040-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000262374.10(ALG1):​c.191C>A​(p.Thr64Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00387 in 1,587,760 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T64I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (16 hom.)
• Consequence: ALG1 ENST00000262374.10 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.87

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009994924).
• BP6: Variant 16-5072040-C-A is Benign according to our data. Variant chr16-5072040-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 193421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00241 (365/151218) while in subpopulation NFE AF= 0.00395 (268/67812). AF 95% confidence interval is 0.00356. There are 0 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG1	NM_019109.5	c.191C>A	p.Thr64Asn	missense_variant	1/13	ENST00000262374.10	NP_061982.3
ALG1	XM_017023457.3	c.191C>A	p.Thr64Asn	missense_variant	1/12		XP_016878946.1
ALG1	XR_007064892.1	n.198C>A		non_coding_transcript_exon_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10	c.191C>A	p.Thr64Asn	missense_variant	1/13	1	NM_019109.5	ENSP00000262374	P1

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 366 AN: 151100 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000901

Gnomad AMI AF: 0.00442

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000854

Gnomad FIN AF: 0.000381

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.00385

GnomAD3 exomes AF: 0.00234 AC: 463 AN: 198180 Hom.: 0 AF XY: 0.00259 AC XY: 279 AN XY: 107732

Gnomad AFR exome AF: 0.000608

Gnomad AMR exome AF: 0.000762

Gnomad ASJ exome AF: 0.00691

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00106

Gnomad FIN exome AF: 0.000457

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.00308

GnomAD4 exome AF: 0.00402 AC: 5776 AN: 1436542 Hom.: 16 Cov.: 31 AF XY: 0.00402 AC XY: 2867 AN XY: 712352

Gnomad4 AFR exome AF: 0.000546

Gnomad4 AMR exome AF: 0.000843

Gnomad4 ASJ exome AF: 0.00829

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.000552

Gnomad4 NFE exome AF: 0.00467

Gnomad4 OTH exome AF: 0.00409

GnomAD4 genome AF: 0.00241 AC: 365 AN: 151218 Hom.: 0 Cov.: 33 AF XY: 0.00196 AC XY: 145 AN XY: 73852

Gnomad4 AFR AF: 0.000899

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000855

Gnomad4 FIN AF: 0.000381

Gnomad4 NFE AF: 0.00395

Gnomad4 OTH AF: 0.00381

Alfa AF: 0.00370 Hom.: 3

Bravo AF: 0.00243

ESP6500AA AF: 0.000234 AC: 1

ESP6500EA AF: 0.00287 AC: 24

ExAC AF: 0.00189 AC: 226

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 26931382) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 01, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 13, 2015

- -

ALG1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2019

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

ALG1-congenital disorder of glycosylation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.083	T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.81	N;.
REVEL	Uncertain	0.33
Sift	Benign	0.079	T;.
Sift4G	Benign	0.28	T;T
Polyphen		0.95	P;.
Vest4		0.61
MVP		0.86
MPC		0.13
ClinPred		0.035	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs145474820; hg19: chr16-5122041;