X-111744768-ACCTCCTCCTCCTCCTCCTCCTCCT-ACCTCCTCCTCCTCCTCCTCCTCCTCCTCCT

Variant names:

• chrX-111744768-A-ACCTCCT
• rs56717389
• NM_001099922.3:c.2830_2835dupCCTCCT

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.2830_2835dupCCTCCT​(p.Pro944_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 0.000419 in 594,036 control chromosomes in the GnomAD database, including 1 homozygotes. There are 31 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., 1 hem., cov: 18)
  • Exomes 𝑓: 0.00038 (1 hom. 30 hem.)
• Consequence: ALG13 NM_001099922.3 conservative_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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-ACCTCCT is Benign according to our data. Variant chrX-111744768-A-ACCTCCT is described in ClinVar as Likely_benign. ClinVar VariationId is 700610.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 = 0.000942 (35/37147) while in subpopulation NFE AF = 0.00136 (27/19912). AF 95% confidence interval is 0.000956. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 30 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.2830_2835dupCCTCCT	p.Pro944_Pro945dup	conservative_inframe_insertion	Exon 24 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.2596_2601dupCCTCCT	p.Pro866_Pro867dup	conservative_inframe_insertion	Exon 24 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.2695+7923_2695+7928dupCCTCCT		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.2830_2835dupCCTCCT	p.Pro944_Pro945dup	conservative_inframe_insertion	Exon 24 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.2806_2811dupCCTCCT	p.Pro936_Pro937dup	conservative_inframe_insertion	Exon 24 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.2656_2661dupCCTCCT	p.Pro886_Pro887dup	conservative_inframe_insertion	Exon 22 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.000942 AC: 35 AN: 37151 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.000503

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000797

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0110

Gnomad NFE AF: 0.00136

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000692 AC: 23 AN: 33243 AF XY: 0.000176

Gnomad AFR exome AF: 0.000714

Gnomad AMR exome AF: 0.000957

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000384 AC: 214 AN: 556889 Hom.: 1 Cov.: 24 AF XY: 0.000189 AC XY: 30 AN XY: 158355

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

African (AFR) AF: 0.000346 AC: 5 AN: 14454

American (AMR) AF: 0.000727 AC: 12 AN: 16512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9522

East Asian (EAS) AF: 0.000325 AC: 5 AN: 15380

South Asian (SAS) AF: 0.000255 AC: 6 AN: 23572

European-Finnish (FIN) AF: 0.0000538 AC: 1 AN: 18588

Middle Eastern (MID) AF: 0.000648 AC: 1 AN: 1544

European-Non Finnish (NFE) AF: 0.000404 AC: 175 AN: 432923

Other (OTH) AF: 0.000369 AC: 9 AN: 24394

⚠️ 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: 0.000942 AC: 35 AN: 37147 Hom.: 0 Cov.: 18 AF XY: 0.000140 AC XY: 1 AN XY: 7145

African (AFR) AF: 0.000503 AC: 5 AN: 9934

American (AMR) AF: 0.000794 AC: 2 AN: 2520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1002

East Asian (EAS) AF: 0.00 AC: 0 AN: 1208

South Asian (SAS) AF: 0.00 AC: 0 AN: 535

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1212

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

European-Non Finnish (NFE) AF: 0.00136 AC: 27 AN: 19912

Other (OTH) AF: 0.00 AC: 0 AN: 429

Alfa AF: 0.00172 Hom.: 38

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ALG13-related disorder (1)
-	-	1	Developmental and epileptic encephalopathy, 36 (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		=89/11	polymorphism

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;