chr16-5077459-T-G

Position:

chr16-5077459-T-G

Variant summary

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

The NM_019109.5(ALG1):c.554T>G(p.Phe185Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,614,118 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 40 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 41 hom. )

Consequence

ALG1
NM_019109.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.81

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=0.008822262).

BP6

Variant 16-5077459-T-G is Benign according to our data. Variant chr16-5077459-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 384255.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 = 0.0126 (1912/152258) while in subpopulation AFR AF= 0.0432 (1797/41550). AF 95% confidence interval is 0.0416. There are 40 homozygotes in gnomad4. There are 915 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALG1	NM_019109.5 linkuse as main transcript	c.554T>G	p.Phe185Cys	missense_variant	5/13	ENST00000262374.10
ALG1	NM_001330504.2 linkuse as main transcript	c.221T>G	p.Phe74Cys	missense_variant	5/13
ALG1	XM_017023457.3 linkuse as main transcript	c.554T>G	p.Phe185Cys	missense_variant	5/12
ALG1	XR_007064892.1 linkuse as main transcript	n.561T>G		non_coding_transcript_exon_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG1	ENST00000262374.10 linkuse as main transcript	c.554T>G	p.Phe185Cys	missense_variant	5/13	1	NM_019109.5	P1	Q9BT22-1

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1902

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0431

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00446

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:

0.000367

Gnomad OTH

AF:

0.00957

GnomAD3 exomes

AF:

0.00337

AC:

848

AN:

251484

Hom.:

AF XY:

0.00258

AC XY:

351

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0437

Gnomad AMR exome

AF:

0.00280

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00145

AC:

2123

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

934

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0463

Gnomad4 AMR exome

AF:

0.00286

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000174

Gnomad4 OTH exome

AF:

0.00369

GnomAD4 genome

AF:

0.0126

AC:

1912

AN:

152258

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

915

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0432

Gnomad4 AMR

AF:

0.00445

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00947

Alfa

AF:

0.00238

Hom.:

Bravo

AF:

0.0146

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0407

AC:

179

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00429

AC:

521

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/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	Aug 31, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ALG1-congenital disorder of glycosylation

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 28, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 25, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.42

.;T;T;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.82

.;T;T;T

MetaRNN

Benign

0.0088

T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.6

.;L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.33

PROVEAN

Pathogenic

-6.2

.;D;.;D

REVEL

Benign

0.24

Sift

Benign

0.11

.;T;.;T

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.074

.;B;.;.

Vest4

0.48

MVP

0.85

MPC

0.057

ClinPred

0.030

GERP RS

-0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.81

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

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