chrX-111759806-A-G

Variant names:

• chrX-111759806-A-G
• rs372990620
• NM_001099922.3:c.3221A>G

Variant summary

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

The NM_001099922.3(ALG13):​c.3221A>G​(p.Tyr1074Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,208,181 control chromosomes in the GnomAD database, including 1 homozygotes. There are 191 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1074F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00032 (1 hom. 185 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.96
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), 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=0.0063561797).
• BP6: Variant X-111759806-A-G is Benign according to our data. Variant chrX-111759806-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 381527.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 = 0.000117 (13/111288) while in subpopulation SAS AF = 0.00421 (11/2610). AF 95% confidence interval is 0.00236. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG13	NM_001099922.3	MANE Select	c.3221A>G	p.Tyr1074Cys	missense	Exon 27 of 27	NP_001093392.1
	ALG13	NM_001257231.2		c.2987A>G	p.Tyr996Cys	missense	Exon 27 of 27	NP_001244160.1
	ALG13	NM_001324292.2		c.2984A>G	p.Tyr995Cys	missense	Exon 26 of 26	NP_001311221.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG13	ENST00000394780.8	TSL:2 MANE Select	c.3221A>G	p.Tyr1074Cys	missense	Exon 27 of 27	ENSP00000378260.3
	ALG13	ENST00000927365.1		c.3197A>G	p.Tyr1066Cys	missense	Exon 27 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.3047A>G	p.Tyr1016Cys	missense	Exon 25 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111233 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00420

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.000675

GnomAD2 exomes AF: 0.000635 AC: 112 AN: 176489 AF XY: 0.00101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000257

Gnomad OTH exome AF: 0.000458

GnomAD4 exome AF: 0.000317 AC: 348 AN: 1096893 Hom.: 1 Cov.: 30 AF XY: 0.000510 AC XY: 185 AN XY: 362491

African (AFR) AF: 0.00 AC: 0 AN: 26389

American (AMR) AF: 0.00 AC: 0 AN: 35073

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19361

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30148

South Asian (SAS) AF: 0.00575 AC: 310 AN: 53908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40466

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4134

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 841384

Other (OTH) AF: 0.000565 AC: 26 AN: 46030

GnomAD4 genome AF: 0.000117 AC: 13 AN: 111288 Hom.: 0 Cov.: 23 AF XY: 0.000179 AC XY: 6 AN XY: 33510

African (AFR) AF: 0.00 AC: 0 AN: 30639

American (AMR) AF: 0.00 AC: 0 AN: 10467

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3515

South Asian (SAS) AF: 0.00421 AC: 11 AN: 2610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5977

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53042

Other (OTH) AF: 0.000666 AC: 1 AN: 1501

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000798 AC: 96

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Developmental and epileptic encephalopathy, 36 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.0
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.083
Sift	Benign	0.13	T
Sift4G	Benign	0.16	T
Polyphen		0.25	B
Vest4		0.19
MutPred		0.26		Loss of phosphorylation at Y1074 (P = 0.0108)
MVP		0.53
MPC		0.22
ClinPred		0.036	T
GERP RS		3.4
PromoterAI		0.0022	Neutral
Varity_R		0.41
gMVP		0.33
Mutation Taster		=96/4	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs372990620; hg19: chrX-111003034; COSMIC: COSV107248493; COSMIC: COSV107248493;