rs370438099

Variant names:

• chrX-111728181-A-G
• rs370438099
• NM_001099922.3:c.2248-4A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001099922.3(ALG13):​c.2248-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,209,347 control chromosomes in the GnomAD database, including 30 homozygotes. There are 1,691 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (14 hom., 111 hem., cov: 23)
  • Exomes 𝑓: 0.0037 (16 hom. 1580 hem.)
• Consequence: ALG13 NM_001099922.3 splice_region, intron
• Scores: Splicing: ADA: 0.004647
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0570
• 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: 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant X-111728181-A-G is Benign according to our data. Variant chrX-111728181-A-G is described in ClinVar as Benign. ClinVar VariationId is 380781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00362 (404/111747) while in subpopulation SAS AF = 0.0154 (41/2670). AF 95% confidence interval is 0.0116. There are 14 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.2248-4A>G		splice_region intron	N/A	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.2014-4A>G		splice_region intron	N/A	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.2248-4A>G		splice_region intron	N/A	NP_001311221.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG13	ENST00000394780.8	TSL:2 MANE Select	c.2248-4A>G		splice_region intron	N/A	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.2224-4A>G		splice_region intron	N/A	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.2074-4A>G		splice_region intron	N/A	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 404 AN: 111692 Hom.: 14 Cov.: 23

Gnomad AFR AF: 0.000521

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.000762

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.000995

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00369

Gnomad OTH AF: 0.00267

GnomAD2 exomes AF: 0.00397 AC: 710 AN: 178742 AF XY: 0.00496

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.000658

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00113

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00338

GnomAD4 exome AF: 0.00366 AC: 4019 AN: 1097600 Hom.: 16 Cov.: 30 AF XY: 0.00435 AC XY: 1580 AN XY: 363120

African (AFR) AF: 0.000189 AC: 5 AN: 26387

American (AMR) AF: 0.000739 AC: 26 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.0188 AC: 1018 AN: 54084

European-Finnish (FIN) AF: 0.00190 AC: 77 AN: 40499

Middle Eastern (MID) AF: 0.00442 AC: 18 AN: 4070

European-Non Finnish (NFE) AF: 0.00324 AC: 2730 AN: 841743

Other (OTH) AF: 0.00310 AC: 143 AN: 46055

GnomAD4 genome AF: 0.00362 AC: 404 AN: 111747 Hom.: 14 Cov.: 23 AF XY: 0.00327 AC XY: 111 AN XY: 33931

African (AFR) AF: 0.000520 AC: 16 AN: 30776

American (AMR) AF: 0.000761 AC: 8 AN: 10516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.0154 AC: 41 AN: 2670

European-Finnish (FIN) AF: 0.000995 AC: 6 AN: 6028

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.00369 AC: 196 AN: 53152

Other (OTH) AF: 0.00263 AC: 4 AN: 1519

Alfa AF: 0.00273 Hom.: 16

Bravo AF: 0.00348

EpiCase AF: 0.00474

EpiControl AF: 0.00518

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Developmental and epileptic encephalopathy, 36 (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	2.7
DANN	Benign	0.80
PhyloP100		0.057
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0046
dbscSNV1_RF	Benign	0.16

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: rs370438099;

hg19: chrX-110971409;