X-111744771-T-A

Variant names:

• chrX-111744771-T-A
• rs13440710
• NM_001099922.3:c.2799T>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001099922.3(ALG13):​c.2799T>A​(p.Pro933Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P933P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (0 hom., 1 hem., cov: 9)
  • Exomes 𝑓: 0.0050 (0 hom. 72 hem.)
• Consequence: ALG13 NM_001099922.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.799
• Publications: 4 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant X-111744771-T-A is Benign according to our data. Variant chrX-111744771-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 412611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.799 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 72 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG13	NM_001099922.3	MANE Select	c.2799T>A	p.Pro933Pro	synonymous	Exon 24 of 27	NP_001093392.1
	ALG13	NM_001257231.2		c.2565T>A	p.Pro855Pro	synonymous	Exon 24 of 27	NP_001244160.1
	ALG13	NM_001324292.2		c.2695+7892T>A		intron	N/A	NP_001311221.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG13	ENST00000394780.8	TSL:2 MANE Select	c.2799T>A	p.Pro933Pro	synonymous	Exon 24 of 27	ENSP00000378260.3
	ALG13	ENST00000470971.5	TSL:5	n.*1791T>A		non_coding_transcript_exon	Exon 19 of 22	ENSP00000479424.2
	ALG13	ENST00000623148.3	TSL:2	n.*2709T>A		non_coding_transcript_exon	Exon 24 of 27	ENSP00000485658.1

Frequencies

GnomAD3 genomes AF: 0.00504 AC: 223 AN: 44241 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00312

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00642

Gnomad SAS AF: 0.0117

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00114

Gnomad OTH AF: 0.00541

GnomAD2 exomes AF: 0.00296 AC: 84 AN: 28366 AF XY: 0.00

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00501 AC: 1089 AN: 217287 Hom.: 0 Cov.: 6 AF XY: 0.00120 AC XY: 72 AN XY: 59767

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

African (AFR) AF: 0.0280 AC: 135 AN: 4816

American (AMR) AF: 0.00490 AC: 34 AN: 6935

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 4 AN: 2981

East Asian (EAS) AF: 0.0433 AC: 184 AN: 4252

South Asian (SAS) AF: 0.0142 AC: 112 AN: 7913

European-Finnish (FIN) AF: 0.0124 AC: 83 AN: 6681

Middle Eastern (MID) AF: 0.00722 AC: 4 AN: 554

European-Non Finnish (NFE) AF: 0.00272 AC: 475 AN: 174518

Other (OTH) AF: 0.00672 AC: 58 AN: 8637

⚠️ 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: 0.00504 AC: 223 AN: 44251 Hom.: 0 Cov.: 9 AF XY: 0.000114 AC XY: 1 AN XY: 8753

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

African (AFR) AF: 0.0161 AC: 158 AN: 9830

American (AMR) AF: 0.00311 AC: 10 AN: 3215

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1228

East Asian (EAS) AF: 0.00641 AC: 9 AN: 1403

South Asian (SAS) AF: 0.0118 AC: 7 AN: 593

European-Finnish (FIN) AF: 0.00480 AC: 7 AN: 1459

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 113

European-Non Finnish (NFE) AF: 0.00114 AC: 29 AN: 25445

Other (OTH) AF: 0.00534 AC: 3 AN: 562

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Developmental and epileptic encephalopathy, 36 (3)
-	-	2	not provided (2)
-	-	1	ALG13-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.61
DANN	Benign	0.39
PhyloP100		-0.80
PromoterAI		-0.0073	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs13440710; hg19: chrX-110987999; COSMIC: COSV52635167; COSMIC: COSV52635167;