Genetic Variant ALG13:p.Pro944_Pro945del (chrX-111744768-ACCTCCT-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001099922.3(ALG13):c.2830_2835delCCTCCT(p.Pro944_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 0.0014 in 591,212 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 209 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., 7 hem., cov: 9)

Exomes 𝑓: 0.0014 ( 0 hom. 202 hem. )

Consequence

ALG13
NM_001099922.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.116

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 -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001099922.3

BP6

Variant X-111744768-ACCTCCT-A is Benign according to our data. Variant chrX-111744768-ACCTCCT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238294.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00194 (72/37153) while in subpopulation SAS AF = 0.00559 (3/537). AF 95% confidence interval is 0.002. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 9. 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.2830_2835delCCTCCT	p.Pro944_Pro945del	conservative_inframe_deletion	Exon 24 of 27	NP_001093392.1	Q9NP73-1
ALG13	NM_001257231.2		c.2596_2601delCCTCCT	p.Pro866_Pro867del	conservative_inframe_deletion	Exon 24 of 27	NP_001244160.1	Q9NP73-3
ALG13	NM_001324292.2		c.2695+7923_2695+7928delCCTCCT		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.2830_2835delCCTCCT	p.Pro944_Pro945del	conservative_inframe_deletion	Exon 24 of 27	ENSP00000378260.3	Q9NP73-1
ALG13	ENST00000927365.1		c.2806_2811delCCTCCT	p.Pro936_Pro937del	conservative_inframe_deletion	Exon 24 of 27	ENSP00000597424.1
ALG13	ENST00000927366.1		c.2656_2661delCCTCCT	p.Pro886_Pro887del	conservative_inframe_deletion	Exon 22 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

AN:

37157

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00160

Gnomad ASJ

AF:

0.000998

Gnomad EAS

AF:

0.000828

Gnomad SAS

AF:

0.00556

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00256

Gnomad OTH

AF:

0.00471

GnomAD2 exomes

AF:

0.00313

AC:

104

AN:

33243

AF XY:

0.00406

show subpopulations

Gnomad AFR exome

AF:

0.00214

Gnomad AMR exome

AF:

0.00465

Gnomad ASJ exome

AF:

0.00193

Gnomad EAS exome

AF:

0.00227

Gnomad FIN exome

AF:

0.00156

Gnomad NFE exome

AF:

0.00213

Gnomad OTH exome

AF:

0.00300

GnomAD4 exome

AF:

0.00137

AC:

757

AN:

554059

Hom.:

AF XY:

0.00129

AC XY:

202

AN XY:

156805

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

14293

American (AMR)

AF:

0.00226

AC:

AN:

16385

Ashkenazi Jewish (ASJ)

AF:

0.00201

AC:

AN:

9451

East Asian (EAS)

AF:

0.00150

AC:

AN:

15315

South Asian (SAS)

AF:

0.00386

AC:

AN:

23306

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

18539

Middle Eastern (MID)

AF:

0.00324

AC:

AN:

1542

European-Non Finnish (NFE)

AF:

0.00119

AC:

513

AN:

430961

Other (OTH)

AF:

0.00152

AC:

AN:

24267

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.430

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

110

<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:

0.00194

AC:

AN:

37153

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

7145

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

9934

American (AMR)

AF:

0.00159

AC:

AN:

2518

Ashkenazi Jewish (ASJ)

AF:

0.000998

AC:

AN:

1002

East Asian (EAS)

AF:

0.000828

AC:

AN:

1208

South Asian (SAS)

AF:

0.00559

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:

0.00256

AC:

AN:

19918

Other (OTH)

AF:

0.00466

AC:

AN:

429

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.00106

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 36 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.12

Mutation Taster

=195/5

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-ACCTCCTCCTCCTCCTCCT

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