16-5072040-C-A

Position:

chr16-5072040-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_019109.5(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
NM_019109.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.87

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
ALG1	NM_019109.5 linkuse as main transcript	c.191C>A	p.Thr64Asn	missense_variant	1/13	ENST00000262374.10
ALG1	XM_017023457.3 linkuse as main transcript	c.191C>A	p.Thr64Asn	missense_variant	1/12
ALG1	XR_007064892.1 linkuse as main transcript	n.198C>A		non_coding_transcript_exon_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG1	ENST00000262374.10 linkuse as main transcript	c.191C>A	p.Thr64Asn	missense_variant	1/13	1	NM_019109.5	P1	Q9BT22-1

Frequencies

GnomAD3 genomes

AF:

0.00242

AC:

366

AN:

151100

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00259

AC XY:

279

AN XY:

107732

show subpopulations

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.:

Cov.:

AF XY:

0.00402

AC XY:

2867

AN XY:

712352

show subpopulations

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.:

Cov.:

AF XY:

0.00196

AC XY:

145

AN XY:

73852

show subpopulations

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.:

Bravo

AF:

0.00243

ESP6500AA

AF:

0.000234

AC:

ESP6500EA

AF:

0.00287

AC:

ExAC

AF:

0.00189

AC:

226

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

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

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.083

T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.80

T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.52

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over