Genetic Variant ALG13:p.Pro943_Pro945dup (chrX-111744768-A-ACCTCCTCCT) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3BP6_ModerateBS2

The NM_001099922.3(ALG13):c.2827_2835dupCCTCCTCCT(p.Pro943_Pro945dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000404 in 594,504 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 0 hem., cov: 18)

Exomes 𝑓: 0.000036 ( 0 hom. 5 hem. )

Consequence

ALG13
NM_001099922.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.159

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, Ambry Genetics, Labcorp Genetics (formerly Invitae), 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 -7 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001099922.3

BP6

Variant X-111744768-A-ACCTCCTCCT is Benign according to our data. Variant chrX-111744768-A-ACCTCCTCCT is described in ClinVar as Likely_benign. ClinVar VariationId is 1593273.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG13	NM_001099922.3 link	c.2827_2835dupCCTCCTCCT	p.Pro943_Pro945dup	conservative_inframe_insertion	Exon 24 of 27	ENST00000394780.8	NP_001093392.1	Q9NP73-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG13	ENST00000394780.8 link	c.2827_2835dupCCTCCTCCT	p.Pro943_Pro945dup	conservative_inframe_insertion	Exon 24 of 27	2	NM_001099922.3	ENSP00000378260.3		Q9NP73-1

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

37159

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000359

AC:

AN:

557345

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

158541

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

14461

American (AMR)

AF:

0.0000605

AC:

AN:

16521

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9524

East Asian (EAS)

AF:

0.0000650

AC:

AN:

15384

South Asian (SAS)

AF:

0.0000424

AC:

AN:

23600

European-Finnish (FIN)

AF:

0.0000538

AC:

AN:

18594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1547

European-Non Finnish (NFE)

AF:

0.0000346

AC:

AN:

433306

Other (OTH)

AF:

0.0000410

AC:

AN:

24408

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000961052), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.355

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:

0.000108

AC:

AN:

37159

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

7145

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000101

AC:

AN:

9937

American (AMR)

AF:

0.00

AC:

AN:

2509

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1002

East Asian (EAS)

AF:

0.00

AC:

AN:

1208

South Asian (SAS)

AF:

0.00

AC:

AN:

540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000151

AC:

AN:

19918

Other (OTH)

AF:

0.00

AC:

AN:

425

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000114836), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.363

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 36

Benign:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.16

Mutation Taster

=89/11

polymorphism

(source)

Splicing

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

Publications

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X-111744768-ACCTCCTCCTCCTCCTCCTCCTCCT-ACCTCCTCCTCCTCCTCCTCCTCCTCCTCCTCCT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over