X-111744768-ACCTCCTCCTCCTCCTCCTCCTCCT-ACCTCCTCCTCCTCCTCCTCCTCCTCCT

Variant names:

• chrX-111744768-A-ACCT
• rs56717389
• NM_001099922.3:c.2833_2835dupCCT

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001099922.3(ALG13):​c.2833_2835dupCCT​(p.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 0.0207 in 575,972 control chromosomes in the GnomAD database, including 34 homozygotes. There are 1,089 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (19 hom., 71 hem., cov: 18)
  • Exomes 𝑓: 0.020 (15 hom. 1018 hem.)
• Consequence: ALG13 NM_001099922.3 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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-A-ACCT is Benign according to our data. Variant chrX-111744768-A-ACCT is described in ClinVar as Benign. ClinVar VariationId is 1168196.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 = 0.0369 (1365/37008) while in subpopulation NFE AF = 0.0508 (1007/19831). AF 95% confidence interval is 0.0482. There are 19 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG13	NM_001099922.3	MANE Select	c.2833_2835dupCCT	p.Pro945dup	conservative_inframe_insertion	Exon 24 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.2599_2601dupCCT	p.Pro867dup	conservative_inframe_insertion	Exon 24 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.2695+7926_2695+7928dupCCT		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_2835dupCCT	p.Pro945dup	conservative_inframe_insertion	Exon 24 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.2809_2811dupCCT	p.Pro937dup	conservative_inframe_insertion	Exon 24 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.2659_2661dupCCT	p.Pro887dup	conservative_inframe_insertion	Exon 22 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 1365 AN: 37012 Hom.: 19 Cov.: 18

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0221

Gnomad AMR AF: 0.0328

Gnomad ASJ AF: 0.0180

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.00926

Gnomad FIN AF: 0.0790

Gnomad MID AF: 0.0110

Gnomad NFE AF: 0.0508

Gnomad OTH AF: 0.0451

GnomAD2 exomes AF: 0.0265 AC: 880 AN: 33243 AF XY: 0.00635

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0243

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.0239

Gnomad FIN exome AF: 0.0297

Gnomad NFE exome AF: 0.0327

Gnomad OTH exome AF: 0.0360

GnomAD4 exome AF: 0.0196 AC: 10546 AN: 538964 Hom.: 15 Cov.: 24 AF XY: 0.00667 AC XY: 1018 AN XY: 152590

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

African (AFR) AF: 0.00694 AC: 99 AN: 14272

American (AMR) AF: 0.0170 AC: 275 AN: 16198

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 107 AN: 9360

East Asian (EAS) AF: 0.00690 AC: 105 AN: 15209

South Asian (SAS) AF: 0.00820 AC: 188 AN: 22917

European-Finnish (FIN) AF: 0.0536 AC: 948 AN: 17686

Middle Eastern (MID) AF: 0.0263 AC: 39 AN: 1481

European-Non Finnish (NFE) AF: 0.0199 AC: 8304 AN: 418198

Other (OTH) AF: 0.0203 AC: 481 AN: 23643

⚠️ 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: 0.0369 AC: 1365 AN: 37008 Hom.: 19 Cov.: 18 AF XY: 0.00997 AC XY: 71 AN XY: 7122

African (AFR) AF: 0.0116 AC: 115 AN: 9912

American (AMR) AF: 0.0330 AC: 83 AN: 2514

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 18 AN: 998

East Asian (EAS) AF: 0.0141 AC: 17 AN: 1206

South Asian (SAS) AF: 0.00931 AC: 5 AN: 537

European-Finnish (FIN) AF: 0.0790 AC: 94 AN: 1190

Middle Eastern (MID) AF: 0.0128 AC: 1 AN: 78

European-Non Finnish (NFE) AF: 0.0508 AC: 1007 AN: 19831

Other (OTH) AF: 0.0424 AC: 18 AN: 425

Alfa AF: 0.0180 Hom.: 38

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Developmental and epileptic encephalopathy, 36 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
Mutation Taster		=88/12	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;