dbSNP rs201055779: ALG13:p.Tyr1003Cys (chrX-111757622-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001099922.3(ALG13):c.3008A>G(p.Tyr1003Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000813 in 1,204,885 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., 7 hem., cov: 22)

Exomes 𝑓: 0.000068 ( 0 hom. 24 hem. )

Consequence

ALG13
NM_001099922.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.785

Publications

0 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01303643).

BP6

Variant X-111757622-A-G is Benign according to our data. Variant chrX-111757622-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 390901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000211 (23/109178) while in subpopulation EAS AF = 0.00145 (5/3454). AF 95% confidence interval is 0.00057. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 7 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.3008A>G	p.Tyr1003Cys	missense	Exon 26 of 27	NP_001093392.1	Q9NP73-1
ALG13	NM_001257231.2		c.2774A>G	p.Tyr925Cys	missense	Exon 26 of 27	NP_001244160.1	Q9NP73-3
ALG13	NM_001324292.2		c.2771A>G	p.Tyr924Cys	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.3008A>G	p.Tyr1003Cys	missense	Exon 26 of 27	ENSP00000378260.3	Q9NP73-1
ALG13	ENST00000927365.1		c.2984A>G	p.Tyr995Cys	missense	Exon 26 of 27	ENSP00000597424.1
ALG13	ENST00000927366.1		c.2834A>G	p.Tyr945Cys	missense	Exon 24 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

109131

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000502

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000100

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00144

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000380

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000154

AC:

AN:

175055

AF XY:

0.000127

show subpopulations

Gnomad AFR exome

AF:

0.000413

Gnomad AMR exome

AF:

0.0000374

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00129

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000259

Gnomad OTH exome

AF:

0.000231

GnomAD4 exome

AF:

0.0000684

AC:

AN:

1095707

Hom.:

Cov.:

AF XY:

0.0000664

AC XY:

AN XY:

361369

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

26315

American (AMR)

AF:

0.0000571

AC:

AN:

35008

Ashkenazi Jewish (ASJ)

AF:

0.0000518

AC:

AN:

19305

East Asian (EAS)

AF:

0.000465

AC:

AN:

30111

South Asian (SAS)

AF:

0.0000372

AC:

AN:

53830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40479

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.0000202

AC:

AN:

840545

Other (OTH)

AF:

0.000739

AC:

AN:

45996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.000211

AC:

AN:

109178

Hom.:

Cov.:

AF XY:

0.000221

AC XY:

AN XY:

31610

show subpopulations

African (AFR)

AF:

0.000501

AC:

AN:

29954

American (AMR)

AF:

0.0000999

AC:

AN:

10010

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2638

East Asian (EAS)

AF:

0.00145

AC:

AN:

3454

South Asian (SAS)

AF:

0.00

AC:

AN:

2508

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.0000380

AC:

AN:

52684

Other (OTH)

AF:

0.00

AC:

AN:

1488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.000343

Hom.:

Bravo

AF:

0.000249

ESP6500AA

AF:

0.000761

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000166

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 36 (2)

not provided (2)

ALG13-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.45

CADD

Benign

7.2

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.69

M_CAP

Benign

0.027

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.7

PhyloP100

0.79

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.087

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.030

Polyphen

0.0030

Vest4

0.26

MVP

0.26

MPC

0.22

ClinPred

0.057

GERP RS

-0.25

Varity_R

0.39

gMVP

0.22

Mutation Taster

=99/1

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