X-111744768-ACCTCCTCCTCCTCCTCCTCCTCCT-ACCTCCTCCTCCTCCTCCTCCT

Variant names:

• chrX-111744768-ACCT-A
• rs56717389
• NM_001099922.3:c.2833_2835delCCT

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_001099922.3(ALG13):​c.2833_2835delCCT​(p.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 0.0483 in 455,685 control chromosomes in the GnomAD database, including 65 homozygotes. There are 1,205 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P945P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.038 (35 hom., 64 hem., cov: 9)
  • Exomes 𝑓: 0.049 (30 hom. 1141 hem.)
• Consequence: ALG13 NM_001099922.3 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.159
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001099922.3
• BP6: Variant X-111744768-ACCT-A is Benign according to our data. Variant chrX-111744768-ACCT-A is described in ClinVar as Benign. ClinVar VariationId is 238295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0965 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG13	NM_001099922.3	MANE Select	c.2833_2835delCCT	p.Pro945del	conservative_inframe_deletion	Exon 24 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.2599_2601delCCT	p.Pro867del	conservative_inframe_deletion	Exon 24 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.2695+7926_2695+7928delCCT		intron	N/A	NP_001311221.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG13	ENST00000394780.8	TSL:2 MANE Select	c.2833_2835delCCT	p.Pro945del	conservative_inframe_deletion	Exon 24 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.2809_2811delCCT	p.Pro937del	conservative_inframe_deletion	Exon 24 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.2659_2661delCCT	p.Pro887del	conservative_inframe_deletion	Exon 22 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.0378 AC: 1398 AN: 37019 Hom.: 35 Cov.: 9

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.0299

Gnomad EAS AF: 0.00995

Gnomad SAS AF: 0.0167

Gnomad FIN AF: 0.00338

Gnomad MID AF: 0.0330

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0447

GnomAD2 exomes AF: 0.0951 AC: 3160 AN: 33243 AF XY: 0.0120

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.132

Gnomad FIN exome AF: 0.0548

Gnomad NFE exome AF: 0.0709

Gnomad OTH exome AF: 0.0941

GnomAD4 exome AF: 0.0493 AC: 20634 AN: 418670 Hom.: 30 AF XY: 0.0109 AC XY: 1141 AN XY: 104424

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

African (AFR) AF: 0.138 AC: 1526 AN: 11048

American (AMR) AF: 0.0731 AC: 900 AN: 12310

Ashkenazi Jewish (ASJ) AF: 0.0837 AC: 515 AN: 6151

East Asian (EAS) AF: 0.0619 AC: 538 AN: 8689

South Asian (SAS) AF: 0.0550 AC: 863 AN: 15680

European-Finnish (FIN) AF: 0.0309 AC: 372 AN: 12032

Middle Eastern (MID) AF: 0.0426 AC: 47 AN: 1103

European-Non Finnish (NFE) AF: 0.0444 AC: 14862 AN: 334505

Other (OTH) AF: 0.0589 AC: 1011 AN: 17152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0377 AC: 1397 AN: 37015 Hom.: 35 Cov.: 9 AF XY: 0.00898 AC XY: 64 AN XY: 7127

African (AFR) AF: 0.102 AC: 1004 AN: 9872

American (AMR) AF: 0.0204 AC: 51 AN: 2502

Ashkenazi Jewish (ASJ) AF: 0.0299 AC: 30 AN: 1002

East Asian (EAS) AF: 0.00995 AC: 12 AN: 1206

South Asian (SAS) AF: 0.0168 AC: 9 AN: 537

European-Finnish (FIN) AF: 0.00338 AC: 4 AN: 1184

Middle Eastern (MID) AF: 0.0256 AC: 2 AN: 78

European-Non Finnish (NFE) AF: 0.0133 AC: 265 AN: 19888

Other (OTH) AF: 0.0466 AC: 20 AN: 429

Alfa AF: 0.0255 Hom.: 38

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Developmental and epileptic encephalopathy, 36 (2)
-	-	2	not specified (2)
-	-	1	ALG13-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
Mutation Taster		=92/8	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs56717389; hg19: chrX-110987996; COSMIC: COSV52635597; COSMIC: COSV52635597;