Genetic Variant NM_001099922.3:c.3221A>G (chrX-111759806-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.3221A>G(p.Tyr1074Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,208,181 control chromosomes in the GnomAD database, including 1 homozygotes. There are 191 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1074F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.00032 ( 1 hom. 185 hem. )

Consequence

ALG13
NM_001099922.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.96

Publications

5 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), 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=0.0063561797).

BP6

Variant X-111759806-A-G is Benign according to our data. Variant chrX-111759806-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 381527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000117 (13/111288) while in subpopulation SAS AF = 0.00421 (11/2610). AF 95% confidence interval is 0.00236. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 23. 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
ALG13	NM_001099922.3	MANE Select	c.3221A>G	p.Tyr1074Cys	missense	Exon 27 of 27	NP_001093392.1
ALG13	NM_001257231.2		c.2987A>G	p.Tyr996Cys	missense	Exon 27 of 27	NP_001244160.1
ALG13	NM_001324292.2		c.2984A>G	p.Tyr995Cys	missense	Exon 26 of 26	NP_001311221.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALG13	ENST00000394780.8	TSL:2 MANE Select	c.3221A>G	p.Tyr1074Cys	missense	Exon 27 of 27	ENSP00000378260.3
ALG13	ENST00000927365.1		c.3197A>G	p.Tyr1066Cys	missense	Exon 27 of 27	ENSP00000597424.1
ALG13	ENST00000927366.1		c.3047A>G	p.Tyr1016Cys	missense	Exon 25 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes

AF:

0.000117

AC:

AN:

111233

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00420

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.000675

GnomAD2 exomes

AF:

0.000635

AC:

112

AN:

176489

AF XY:

0.00101

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000257

Gnomad OTH exome

AF:

0.000458

GnomAD4 exome

AF:

0.000317

AC:

348

AN:

1096893

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

185

AN XY:

362491

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26389

American (AMR)

AF:

0.00

AC:

AN:

35073

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19361

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30148

South Asian (SAS)

AF:

0.00575

AC:

310

AN:

53908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40466

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

841384

Other (OTH)

AF:

0.000565

AC:

AN:

46030

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:

0.000117

AC:

AN:

111288

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

AN XY:

33510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30639

American (AMR)

AF:

0.00

AC:

AN:

10467

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3515

South Asian (SAS)

AF:

0.00421

AC:

AN:

2610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5977

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

53042

Other (OTH)

AF:

0.000666

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.0000434

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000798

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 36 (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.64

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.7

PhyloP100

2.0

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.083

Sift

Benign

0.13

Sift4G

Benign

0.16

Polyphen

0.25

Vest4

0.19

MutPred

0.26

Loss of phosphorylation at Y1074 (P = 0.0108)

MVP

0.53

MPC

0.22

ClinPred

0.036

GERP RS

3.4

PromoterAI

0.0022

Neutral

(source)

Varity_R

0.41

gMVP

0.33

Mutation Taster

=96/4

polymorphism (auto)

(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