Genetic Variant ALG13:p.Leu611Phe (chrX-111726910-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001099922.3(ALG13):c.1831C>T(p.Leu611Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000852 in 1,209,548 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L611V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000081 ( 0 hom. 31 hem. )

Consequence

ALG13
NM_001099922.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 0.555

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08960262).

BP6

Variant X-111726910-C-T is Benign according to our data. Variant chrX-111726910-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 508540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000126 (14/111509) while in subpopulation NFE AF = 0.000245 (13/53136). AF 95% confidence interval is 0.000144. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 4 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.1831C>T	p.Leu611Phe	missense	Exon 16 of 27	NP_001093392.1	Q9NP73-1
ALG13	NM_001257231.2		c.1597C>T	p.Leu533Phe	missense	Exon 16 of 27	NP_001244160.1	Q9NP73-3
ALG13	NM_001324292.2		c.1831C>T	p.Leu611Phe	missense	Exon 16 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.1831C>T	p.Leu611Phe	missense	Exon 16 of 27	ENSP00000378260.3	Q9NP73-1
ALG13	ENST00000927365.1		c.1831C>T	p.Leu611Phe	missense	Exon 16 of 27	ENSP00000597424.1
ALG13	ENST00000927366.1		c.1657C>T	p.Leu553Phe	missense	Exon 14 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes

AF:

0.000126

AC:

AN:

111509

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000950

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:

0.000245

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000502

AC:

AN:

179198

AF XY:

0.0000299

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:

0.000101

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.0000811

AC:

AN:

1098039

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

363479

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54145

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40523

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000986

AC:

AN:

841960

Other (OTH)

AF:

0.000109

AC:

AN:

46078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.000126

AC:

AN:

111509

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

33687

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30572

American (AMR)

AF:

0.0000950

AC:

AN:

10527

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3553

South Asian (SAS)

AF:

0.00

AC:

AN:

2621

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6037

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.000245

AC:

AN:

53136

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000111

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000364

AC:

ExAC

AF:

0.0000747

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 36 (1)

not specified (1)

Congenital disorder of glycosylation;C3463992:Developmental and epileptic encephalopathy, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.40

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.090

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.0

PhyloP100

0.56

PrimateAI

Benign

0.26

PROVEAN

Benign

-2.1

REVEL

Benign

0.028

Sift

Uncertain

0.028

Sift4G

Uncertain

0.044

Polyphen

0.062

Vest4

0.25

MVP

0.19

MPC

0.31

ClinPred

0.015

GERP RS

1.5

Varity_R

0.13

gMVP

0.30

Mutation Taster

=95/5

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