Genetic Variant ALG13:p.Pro941_Pro945del (chrX-111744768-ACCTCCTCCTCCTCCT-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_001099922.3(ALG13):c.2821_2835delCCTCCTCCTCCTCCT(p.Pro941_Pro945del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 594,505 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 28 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., 2 hem., cov: 9)

Exomes 𝑓: 0.00017 ( 0 hom. 26 hem. )

Consequence

ALG13
NM_001099922.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.322

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001099922.3

BP6

Variant X-111744768-ACCTCCTCCTCCTCCT-A is Benign according to our data. Variant chrX-111744768-ACCTCCTCCTCCTCCT-A is described in ClinVar as Likely_benign. ClinVar VariationId is 833675.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 = 0.000323 (12/37154) while in subpopulation EAS AF = 0.000828 (1/1208). AF 95% confidence interval is 0.00014. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 9. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 2 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.2821_2835delCCTCCTCCTCCTCCT	p.Pro941_Pro945del	conservative_inframe_deletion	Exon 24 of 27	NP_001093392.1	Q9NP73-1
ALG13	NM_001257231.2		c.2587_2601delCCTCCTCCTCCTCCT	p.Pro863_Pro867del	conservative_inframe_deletion	Exon 24 of 27	NP_001244160.1	Q9NP73-3
ALG13	NM_001324292.2		c.2695+7914_2695+7928delCCTCCTCCTCCTCCT		intron	N/A	NP_001311221.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG13	ENST00000394780.8	TSL:2 MANE Select	c.2821_2835delCCTCCTCCTCCTCCT	p.Pro941_Pro945del	conservative_inframe_deletion	Exon 24 of 27	ENSP00000378260.3	Q9NP73-1
ALG13	ENST00000927365.1		c.2797_2811delCCTCCTCCTCCTCCT	p.Pro933_Pro937del	conservative_inframe_deletion	Exon 24 of 27	ENSP00000597424.1
ALG13	ENST00000927366.1		c.2647_2661delCCTCCTCCTCCTCCT	p.Pro883_Pro887del	conservative_inframe_deletion	Exon 22 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes

AF:

0.000323

AC:

AN:

37158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000302

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000798

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000828

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000301

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000167

AC:

AN:

557351

Hom.:

AF XY:

0.000164

AC XY:

AN XY:

158549

show subpopulations

African (AFR)

AF:

0.000277

AC:

AN:

14462

American (AMR)

AF:

0.000121

AC:

AN:

16517

Ashkenazi Jewish (ASJ)

AF:

0.000105

AC:

AN:

9522

East Asian (EAS)

AF:

0.0000650

AC:

AN:

15382

South Asian (SAS)

AF:

0.000254

AC:

AN:

23601

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

18593

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1547

European-Non Finnish (NFE)

AF:

0.000155

AC:

AN:

433315

Other (OTH)

AF:

0.000205

AC:

AN:

24412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.000323

AC:

AN:

37154

Hom.:

Cov.:

AF XY:

0.000280

AC XY:

AN XY:

7144

show subpopulations

African (AFR)

AF:

0.000302

AC:

AN:

9936

American (AMR)

AF:

0.000794

AC:

AN:

2518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1002

East Asian (EAS)

AF:

0.000828

AC:

AN:

1208

South Asian (SAS)

AF:

0.00

AC:

AN:

537

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000301

AC:

AN:

19917

Other (OTH)

AF:

0.00

AC:

AN:

429

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

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:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 36 (2)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.32

Mutation Taster

=188/12

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-ACCTCCTCCT

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