rs1057522541

Variant names:

• chrX-111718241-C-T
• rs1057522541
• NM_001099922.3:c.1217C>T
• ALG13 p.Ala406Val

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001099922.3(ALG13):​c.1217C>T​(p.Ala406Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000252 in 1,192,332 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.0440
• 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056467623).
• BP6: Variant X-111718241-C-T is Benign according to our data. Variant chrX-111718241-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 386580.

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.1217C>T	p.Ala406Val	missense	Exon 10 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.983C>T	p.Ala328Val	missense	Exon 10 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.1217C>T	p.Ala406Val	missense	Exon 10 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.1217C>T	p.Ala406Val	missense	Exon 10 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.1217C>T	p.Ala406Val	missense	Exon 10 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.1217C>T	p.Ala406Val	missense	Exon 10 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.00000901 AC: 1 AN: 110971 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000961

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1081361 Hom.: 0 Cov.: 29 AF XY: 0.00000285 AC XY: 1 AN XY: 351457

African (AFR) AF: 0.00 AC: 0 AN: 26155

American (AMR) AF: 0.0000602 AC: 2 AN: 33227

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18961

East Asian (EAS) AF: 0.00 AC: 0 AN: 29804

South Asian (SAS) AF: 0.00 AC: 0 AN: 51217

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 832717

Other (OTH) AF: 0.00 AC: 0 AN: 45510

GnomAD4 genome AF: 0.00000901 AC: 1 AN: 110971 Hom.: 0 Cov.: 22 AF XY: 0.0000301 AC XY: 1 AN XY: 33211

African (AFR) AF: 0.00 AC: 0 AN: 30499

American (AMR) AF: 0.0000961 AC: 1 AN: 10406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00 AC: 0 AN: 2620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52980

Other (OTH) AF: 0.00 AC: 0 AN: 1486

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 36 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.86
DANN	Benign	0.89
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.22	N
PhyloP100		0.044
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.023
Sift	Benign	0.38	T
Sift4G	Uncertain	0.0070	D
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.13
Mutation Taster		=93/7	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057522541;

hg19: chrX-110961469;

COSMIC: COSV52638497;

COSMIC: COSV52638497;