chrX-111720148-A-G

Variant names:

• chrX-111720148-A-G
• rs747478031
• NM_001099922.3:c.1304A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001099922.3(ALG13):​c.1304A>G​(p.Asn435Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,186,141 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N435K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.000042 (0 hom. 8 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.420
• 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: 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073872507).
• BP6: Variant X-111720148-A-G is Benign according to our data. Variant chrX-111720148-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 373473.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000446 (5/112061) while in subpopulation AMR AF = 0.000472 (5/10595). AF 95% confidence interval is 0.000185. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 4 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.1304A>G	p.Asn435Ser	missense	Exon 11 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.1070A>G	p.Asn357Ser	missense	Exon 11 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.1304A>G	p.Asn435Ser	missense	Exon 11 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.1304A>G	p.Asn435Ser	missense	Exon 11 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.1304A>G	p.Asn435Ser	missense	Exon 11 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.1304A>G	p.Asn435Ser	missense	Exon 11 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112009 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000472

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

GnomAD2 exomes AF: 0.000207 AC: 31 AN: 149947 AF XY: 0.000113

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000419 AC: 45 AN: 1074080 Hom.: 0 Cov.: 26 AF XY: 0.0000233 AC XY: 8 AN XY: 343352

African (AFR) AF: 0.00 AC: 0 AN: 25720

American (AMR) AF: 0.00116 AC: 38 AN: 32739

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18790

East Asian (EAS) AF: 0.00 AC: 0 AN: 29787

South Asian (SAS) AF: 0.00 AC: 0 AN: 49843

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39697

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4045

European-Non Finnish (NFE) AF: 0.00000845 AC: 7 AN: 828207

Other (OTH) AF: 0.00 AC: 0 AN: 45252

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 112061 Hom.: 0 Cov.: 23 AF XY: 0.000117 AC XY: 4 AN XY: 34211

African (AFR) AF: 0.00 AC: 0 AN: 30836

American (AMR) AF: 0.000472 AC: 5 AN: 10595

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3572

South Asian (SAS) AF: 0.00 AC: 0 AN: 2700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53199

Other (OTH) AF: 0.00 AC: 0 AN: 1527

Alfa AF: 0.0000524 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000168 AC: 20

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Developmental and epileptic encephalopathy, 36 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.0030
DANN	Benign	0.60
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.42
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.053
Sift	Benign	0.52	T
Sift4G	Benign	0.11	T
Polyphen		0.0010	B
Vest4		0.039
MutPred		0.19		Loss of loop (P = 0.0374)
MVP		0.26
MPC		0.14
ClinPred		0.021	T
GERP RS		-8.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.094
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs747478031; hg19: chrX-110963376;