16-5075447-C-G

Position:

chr16-5075447-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1PM2PP3PP5_Moderate

The NM_019109.5(ALG1):c.450C>G(p.Ser150Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ALG1
NM_019109.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.38

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:

ALG1 (HGNC:):

ALG1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS1

Transcript NM_019109.5 (ALG1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

PP5

Variant 16-5075447-C-G is Pathogenic according to our data. Variant chr16-5075447-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 4726.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-5075447-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG1	NM_019109.5 linkuse as main transcript	c.450C>G	p.Ser150Arg	missense_variant	4/13	ENST00000262374.10	NP_061982.3	Q9BT22-1
ALG1	NM_001330504.2 linkuse as main transcript	c.117C>G	p.Ser39Arg	missense_variant	4/13		NP_001317433.1	Q9BT22-2
ALG1	XM_017023457.3 linkuse as main transcript	c.450C>G	p.Ser150Arg	missense_variant	4/12		XP_016878946.1	A0A804HJL6
ALG1	XR_007064892.1 linkuse as main transcript	n.457C>G		non_coding_transcript_exon_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10 linkuse as main transcript	c.450C>G	p.Ser150Arg	missense_variant	4/13	1	NM_019109.5	ENSP00000262374.5		Q9BT22-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251492

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ALG1-congenital disorder of glycosylation

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 29, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALG1 function (PMID: 14709599). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ALG1 protein function. ClinVar contains an entry for this variant (Variation ID: 4726). This missense change has been observed in individual(s) with ALG1-congenital disorder of glycosylation (PMID: 14709599, 20679665, 26931382). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 150 of the ALG1 protein (p.Ser150Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.085

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.21

M_CAP

Benign

0.052

MetaRNN

Pathogenic

0.77

Sift4G

Benign

1.0

MVP

0.82

ClinPred

0.92

GERP RS

5.7

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

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