X-111744768-ACCTCCTCCTCCTCCTCCTCCTCCT-ACCTCCTCCTCCTCCTCCTCCTCCTCCTCCTCCT

Variant names:

• chrX-111744768-A-ACCTCCTCCT
• rs56717389
• NM_001099922.3:c.2827_2835dupCCTCCTCCT

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_001099922.3(ALG13):​c.2827_2835dupCCTCCTCCT​(p.Pro943_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 0.0000404 in 594,504 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 0 hem., cov: 18)
  • Exomes 𝑓: 0.000036 (0 hom. 5 hem.)
• Consequence: ALG13 NM_001099922.3 conservative_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001099922.3
• BP6: Variant X-111744768-A-ACCTCCTCCT is Benign according to our data. Variant chrX-111744768-A-ACCTCCTCCT is described in ClinVar as Likely_benign. ClinVar VariationId is 1593273.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 5 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.2827_2835dupCCTCCTCCT	p.Pro943_Pro945dup	conservative_inframe_insertion	Exon 24 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.2593_2601dupCCTCCTCCT	p.Pro865_Pro867dup	conservative_inframe_insertion	Exon 24 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.2695+7920_2695+7928dupCCTCCTCCT		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.2827_2835dupCCTCCTCCT	p.Pro943_Pro945dup	conservative_inframe_insertion	Exon 24 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.2803_2811dupCCTCCTCCT	p.Pro935_Pro937dup	conservative_inframe_insertion	Exon 24 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.2653_2661dupCCTCCTCCT	p.Pro885_Pro887dup	conservative_inframe_insertion	Exon 22 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.000108 AC: 4 AN: 37159 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.000101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000359 AC: 20 AN: 557345 Hom.: 0 Cov.: 24 AF XY: 0.0000315 AC XY: 5 AN XY: 158541

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

African (AFR) AF: 0.00 AC: 0 AN: 14461

American (AMR) AF: 0.0000605 AC: 1 AN: 16521

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9524

East Asian (EAS) AF: 0.0000650 AC: 1 AN: 15384

South Asian (SAS) AF: 0.0000424 AC: 1 AN: 23600

European-Finnish (FIN) AF: 0.0000538 AC: 1 AN: 18594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1547

European-Non Finnish (NFE) AF: 0.0000346 AC: 15 AN: 433306

Other (OTH) AF: 0.0000410 AC: 1 AN: 24408

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000961052), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000108 AC: 4 AN: 37159 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 7145

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

African (AFR) AF: 0.000101 AC: 1 AN: 9937

American (AMR) AF: 0.00 AC: 0 AN: 2509

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: 540

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 91

European-Non Finnish (NFE) AF: 0.000151 AC: 3 AN: 19918

Other (OTH) AF: 0.00 AC: 0 AN: 425

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000114836), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 38

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 36 (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;