rs747478031

chrX-111720148-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001099922.3(ALG13):c.1304A>G(p.Asn435Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,186,141 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N435K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000042 ( 0 hom. 8 hem. )

Consequence

ALG13
NM_001099922.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.420

Variant links:

Genes affected

ALG13 (HGNC:30881): (ALG13 UDP-N-acetylglucosaminyltransferase subunit) The protein encoded by this gene is a subunit of a bipartite UDP-N-acetylglucosamine transferase. It heterodimerizes with asparagine-linked glycosylation 14 homolog to form a functional UDP-GlcNAc glycosyltransferase that catalyzes the second sugar addition of the highly conserved oligosaccharide precursor in endoplasmic reticulum N-linked glycosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

ALG13 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073872507).

BP6

Variant X-111720148-A-G is Benign according to our data. Variant chrX-111720148-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 373473.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000446 (5/112061) while in subpopulation AMR AF= 0.000472 (5/10595). AF 95% confidence interval is 0.000185. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG13	NM_001099922.3 linkuse as main transcript	c.1304A>G	p.Asn435Ser	missense_variant	11/27	ENST00000394780.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG13	ENST00000394780.8 linkuse as main transcript	c.1304A>G	p.Asn435Ser	missense_variant	11/27	2	NM_001099922.3	A2	Q9NP73-1

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112009

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34149

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000472

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:

0.000207

AC:

AN:

149947

Hom.:

AF XY:

0.000113

AC XY:

AN XY:

44079

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00132

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:

0.0000419

AC:

AN:

1074080

Hom.:

Cov.:

AF XY:

0.0000233

AC XY:

AN XY:

343352

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000845

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000446

AC:

AN:

112061

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34211

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000472

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

Alfa

AF:

0.0000844

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000168

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 22, 2016

A variant of uncertain significance has been identified in the ALG13 gene. The N435S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N435S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. However, this variant was not observed in approximately 5,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Developmental and epileptic encephalopathy, 36

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.99

Cadd

Benign

0.0030

Dann

Benign

0.60

DEOGEN2

Benign

0.20

T;.;.;.;.;T

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.48

T;T;.;T;.;T

M_CAP

Benign

0.0091

MetaRNN

Benign

0.0074

T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.55

N;.;.;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.75

N;.;N;.;.;.

REVEL

Benign

0.053

Sift

Benign

0.52

T;.;T;.;.;.

Sift4G

Benign

0.11

T;T;T;T;T;T

Polyphen

0.0010

B;B;B;B;B;.

Vest4

0.039

MutPred

0.19

Loss of loop (P = 0.0374);.;.;.;.;.;

MVP

0.26

MPC

0.14

ClinPred

0.021

GERP RS

-8.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.027

gMVP

0.094

Splicing

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