chrX-111682233-C-T

Variant names:

• chrX-111682233-C-T
• rs146925326
• NM_001099922.3:c.183C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001257231.2(ALG13):​c.8C>T​(p.Thr3Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,197,624 control chromosomes in the GnomAD database, including 139 homozygotes. There are 5,188 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T3T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0092 (12 hom., 281 hem., cov: 23)
  • Exomes 𝑓: 0.015 (127 hom. 4907 hem.)
• Consequence: ALG13 NM_001257231.2 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.657
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039321184).
• BP6: Variant X-111682233-C-T is Benign according to our data. Variant chrX-111682233-C-T is described in ClinVar as Benign. ClinVar VariationId is 238290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00923 (1035/112115) while in subpopulation NFE AF = 0.0165 (877/53223). AF 95% confidence interval is 0.0156. There are 12 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257231.2. 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.183C>T	p.Tyr61Tyr	synonymous	Exon 2 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.8C>T	p.Thr3Ile	missense splice_region	Exon 2 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001257241.3		c.8C>T	p.Thr3Ile	missense splice_region	Exon 2 of 4	NP_001244170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG13	ENST00000394780.8	TSL:2 MANE Select	c.183C>T	p.Tyr61Tyr	synonymous	Exon 2 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000371979.7	TSL:1	c.183C>T	p.Tyr61Tyr	synonymous	Exon 2 of 4	ENSP00000361047.3	Q9NP73-2
	ALG13	ENST00000927365.1		c.183C>T	p.Tyr61Tyr	synonymous	Exon 2 of 27	ENSP00000597424.1

Frequencies

GnomAD3 genomes AF: 0.00925 AC: 1036 AN: 112060 Hom.: 12 Cov.: 23

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00198

Gnomad ASJ AF: 0.00264

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00114

Gnomad FIN AF: 0.00850

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.00397

GnomAD2 exomes AF: 0.00809 AC: 1393 AN: 172113 AF XY: 0.00763

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.00305

Gnomad ASJ exome AF: 0.000990

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00824

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.0146 AC: 15858 AN: 1085509 Hom.: 127 Cov.: 29 AF XY: 0.0139 AC XY: 4907 AN XY: 352453

African (AFR) AF: 0.00196 AC: 51 AN: 26031

American (AMR) AF: 0.00311 AC: 106 AN: 34113

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 38 AN: 19057

East Asian (EAS) AF: 0.00 AC: 0 AN: 29699

South Asian (SAS) AF: 0.00129 AC: 67 AN: 51758

European-Finnish (FIN) AF: 0.00892 AC: 359 AN: 40267

Middle Eastern (MID) AF: 0.000490 AC: 2 AN: 4078

European-Non Finnish (NFE) AF: 0.0176 AC: 14677 AN: 834956

Other (OTH) AF: 0.0123 AC: 558 AN: 45550

GnomAD4 genome AF: 0.00923 AC: 1035 AN: 112115 Hom.: 12 Cov.: 23 AF XY: 0.00819 AC XY: 281 AN XY: 34293

African (AFR) AF: 0.00223 AC: 69 AN: 30873

American (AMR) AF: 0.00198 AC: 21 AN: 10618

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 7 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00114 AC: 3 AN: 2635

European-Finnish (FIN) AF: 0.00850 AC: 52 AN: 6120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0165 AC: 877 AN: 53223

Other (OTH) AF: 0.00392 AC: 6 AN: 1530

Alfa AF: 0.00719 Hom.: 91

Bravo AF: 0.00844

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0145 AC: 42

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.0162 AC: 109

ExAC AF: 0.00893 AC: 1084

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.52
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0039	T
PhyloP100		0.66
Sift4G	Pathogenic	0.0010	D
Polyphen		0.082	B
Vest4		0.049
MVP		0.49
GERP RS		4.3
PromoterAI		-0.015	Neutral
Mutation Taster		=288/12	polymorphism (auto)

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: rs146925326; hg19: chrX-110925461; COSMIC: COSV106087355;