dbSNP rs773401427: ALG13:p.Ala1048Gly (chrX-111757757-C-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001099922.3(ALG13):c.3143C>G(p.Ala1048Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,203,211 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., 6 hem., cov: 22)

Exomes 𝑓: 0.000023 ( 0 hom. 6 hem. )

Consequence

ALG13
NM_001099922.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.938

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 36
Inheritance: XL Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ALG13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.034623653).

BP6

Variant X-111757757-C-G is Benign according to our data. Variant chrX-111757757-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 383411.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000252 (28/111243) while in subpopulation AMR AF = 0.0027 (28/10377). AF 95% confidence interval is 0.00192. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 6 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099922.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG13	NM_001099922.3	MANE Select	c.3143C>G	p.Ala1048Gly	missense	Exon 26 of 27	NP_001093392.1	Q9NP73-1
ALG13	NM_001257231.2		c.2909C>G	p.Ala970Gly	missense	Exon 26 of 27	NP_001244160.1	Q9NP73-3
ALG13	NM_001324292.2		c.2906C>G	p.Ala969Gly	missense	Exon 25 of 26	NP_001311221.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG13	ENST00000394780.8	TSL:2 MANE Select	c.3143C>G	p.Ala1048Gly	missense	Exon 26 of 27	ENSP00000378260.3	Q9NP73-1
ALG13	ENST00000927365.1		c.3119C>G	p.Ala1040Gly	missense	Exon 26 of 27	ENSP00000597424.1
ALG13	ENST00000927366.1		c.2969C>G	p.Ala990Gly	missense	Exon 24 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes

AF:

0.000252

AC:

AN:

111243

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00270

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

GnomAD2 exomes

AF:

0.0000236

AC:

AN:

169590

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000778

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000477

GnomAD4 exome

AF:

0.0000229

AC:

AN:

1091968

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

358082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26174

American (AMR)

AF:

0.000379

AC:

AN:

34264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19055

East Asian (EAS)

AF:

0.00

AC:

AN:

30086

South Asian (SAS)

AF:

0.00

AC:

AN:

52740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40431

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4056

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839325

Other (OTH)

AF:

0.000240

AC:

AN:

45837

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000252

AC:

AN:

111243

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

AN XY:

33433

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30604

American (AMR)

AF:

0.00270

AC:

AN:

10377

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3547

South Asian (SAS)

AF:

0.00

AC:

AN:

2645

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5931

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53085

Other (OTH)

AF:

0.00

AC:

AN:

1489

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000574

ExAC

AF:

0.0000332

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Developmental and epileptic encephalopathy, 36 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.61

M_CAP

Benign

0.0088

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

0.94

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.4

REVEL

Benign

0.024

Sift

Benign

0.15

Sift4G

Benign

0.17

Polyphen

0.0010

Vest4

0.040

MutPred

0.11

Loss of sheet (P = 0.0315)

MVP

0.40

MPC

0.18

ClinPred

0.049

GERP RS

2.4

Varity_R

0.073

gMVP

0.15

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over