rs374748006

chrX-111708281-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001099922.3(ALG13):c.638G>A(p.Ser213Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000076 in 1,210,094 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., 12 hem., cov: 23)
  • Exomes 𝑓: 0.000042 (0 hom. 14 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.83

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-AS1 (HGNC:41277): (ALG13 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013918281).
• BP6: Variant X-111708281-G-A is Benign according to our data. Variant chrX-111708281-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 381446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000411 (46/112019) while in subpopulation AMR AF= 0.00398 (42/10562). AF 95% confidence interval is 0.00302. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG13	NM_001099922.3	c.638G>A	p.Ser213Asn	missense_variant	4/27	ENST00000394780.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG13	ENST00000394780.8	c.638G>A	p.Ser213Asn	missense_variant	4/27	2	NM_001099922.3	A2
ALG13-AS1	ENST00000430794.1	n.107-1544C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000411 AC: 46 AN: 111964 Hom.: 0 Cov.: 23 AF XY: 0.000352 AC XY: 12 AN XY: 34138

Gnomad AFR AF: 0.0000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00398

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: 0.00133

GnomAD3 exomes AF: 0.0000558 AC: 10 AN: 179278 Hom.: 0 AF XY: 0.0000597 AC XY: 4 AN XY: 67000

Gnomad AFR exome AF: 0.0000810

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000253

Gnomad OTH exome AF: 0.000899

GnomAD4 exome AF: 0.0000419 AC: 46 AN: 1098075 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 14 AN XY: 363501

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000483

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000131

Gnomad4 OTH exome AF: 0.000369

GnomAD4 genome AF: 0.000411 AC: 46 AN: 112019 Hom.: 0 Cov.: 23 AF XY: 0.000351 AC XY: 12 AN XY: 34203

Gnomad4 AFR AF: 0.0000649

Gnomad4 AMR AF: 0.00398

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.00107

ESP6500AA AF: 0.000381 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000831 AC: 10

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 36 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ALG13-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;.;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.69	T;T;.;T;.
MetaRNN	Benign	0.014	T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.34	N;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.63	N;.;N;.;.
REVEL	Benign	0.080
Sift	Benign	0.14	T;.;T;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.20	B;B;B;B;B
Vest4		0.13
MVP		0.50
MPC		0.17
ClinPred		0.013	T
GERP RS		5.7
Varity_R		0.087
gMVP		0.12

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs374748006; hg19: chrX-110951509;