rs398122394

Variant names:

• chrX-111685040-A-G
• rs398122394
• NM_001099922.3:c.320A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-111685040-A-G
• chrX-111685040-A-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PM5 PP5_Very_Strong

The NM_001099922.3(ALG13):​c.320A>G​(p.Asn107Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N107K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 8.51
• Publications: 38 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-111685040-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 870209.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant X-111685040-A-G is Pathogenic according to our data. Variant chrX-111685040-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 66086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.320A>G	p.Asn107Ser	missense	Exon 3 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.86A>G	p.Asn29Ser	missense	Exon 3 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.320A>G	p.Asn107Ser	missense	Exon 3 of 26	NP_001311221.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG13	ENST00000394780.8	TSL:2 MANE Select	c.320A>G	p.Asn107Ser	missense	Exon 3 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000371979.7	TSL:1	c.320A>G	p.Asn107Ser	missense	Exon 3 of 4	ENSP00000361047.3	Q9NP73-2
	ALG13	ENST00000927365.1		c.320A>G	p.Asn107Ser	missense	Exon 3 of 27	ENSP00000597424.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	Developmental and epileptic encephalopathy, 36 (13)
6	-	-	not provided (6)
3	-	-	Intellectual disability (3)
1	-	-	ALG13-related disorder (1)
1	-	-	Hypotonia;C0036572:Seizure;C4022738:Neurodevelopmental delay;C4551563:Microcephaly (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Rare genetic intellectual disability (1)
1	-	-	Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.49	T
PhyloP100		8.5
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.029	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.60		Gain of disorder (P = 0.0968)
MVP		0.74
MPC		0.64
ClinPred		0.98	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.29
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs398122394; hg19: chrX-110928268;