rs5985637

Variant names:

• chrX-111720110-T-C
• rs5985637
• NM_001099922.3:c.1266T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001099922.3(ALG13):​c.1266T>C​(p.Gly422Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,188,699 control chromosomes in the GnomAD database, including 162 homozygotes. There are 5,887 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (32 hom., 411 hem., cov: 23)
  • Exomes 𝑓: 0.017 (130 hom. 5476 hem.)
• Consequence: ALG13 NM_001099922.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.78
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant X-111720110-T-C is Benign according to our data. Variant chrX-111720110-T-C is described in ClinVar as Benign. ClinVar VariationId is 238289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0135 (1516/112035) while in subpopulation AMR AF = 0.0239 (254/10608). AF 95% confidence interval is 0.0215. There are 32 homozygotes in GnomAd4. There are 411 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 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.1266T>C	p.Gly422Gly	synonymous	Exon 11 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.1032T>C	p.Gly344Gly	synonymous	Exon 11 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.1266T>C	p.Gly422Gly	synonymous	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.1266T>C	p.Gly422Gly	synonymous	Exon 11 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.1266T>C	p.Gly422Gly	synonymous	Exon 11 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.1266T>C	p.Gly422Gly	synonymous	Exon 11 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 1515 AN: 111980 Hom.: 32 Cov.: 23

Gnomad AFR AF: 0.00221

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.00908

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00148

Gnomad FIN AF: 0.00347

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.0146

GnomAD2 exomes AF: 0.0110 AC: 1680 AN: 152142 AF XY: 0.00957

Gnomad AFR exome AF: 0.00217

Gnomad AMR exome AF: 0.0130

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0120

GnomAD4 exome AF: 0.0170 AC: 18322 AN: 1076664 Hom.: 130 Cov.: 25 AF XY: 0.0158 AC XY: 5476 AN XY: 346094

African (AFR) AF: 0.00232 AC: 60 AN: 25829

American (AMR) AF: 0.0138 AC: 456 AN: 33133

Ashkenazi Jewish (ASJ) AF: 0.0154 AC: 290 AN: 18847

East Asian (EAS) AF: 0.0000335 AC: 1 AN: 29885

South Asian (SAS) AF: 0.00258 AC: 130 AN: 50305

European-Finnish (FIN) AF: 0.00462 AC: 184 AN: 39813

Middle Eastern (MID) AF: 0.0176 AC: 71 AN: 4042

European-Non Finnish (NFE) AF: 0.0198 AC: 16398 AN: 829505

Other (OTH) AF: 0.0162 AC: 732 AN: 45305

GnomAD4 genome AF: 0.0135 AC: 1516 AN: 112035 Hom.: 32 Cov.: 23 AF XY: 0.0120 AC XY: 411 AN XY: 34215

African (AFR) AF: 0.00220 AC: 68 AN: 30842

American (AMR) AF: 0.0239 AC: 254 AN: 10608

Ashkenazi Jewish (ASJ) AF: 0.00908 AC: 24 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.00185 AC: 5 AN: 2701

European-Finnish (FIN) AF: 0.00347 AC: 21 AN: 6054

Middle Eastern (MID) AF: 0.0278 AC: 6 AN: 216

European-Non Finnish (NFE) AF: 0.0184 AC: 980 AN: 53191

Other (OTH) AF: 0.0144 AC: 22 AN: 1531

Alfa AF: 0.0115 Hom.: 202

Bravo AF: 0.0147

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.5
DANN	Benign	0.91
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs5985637; hg19: chrX-110963338; COSMIC: COSV52639057;