11-78112745-C-T

Variant names:

• chr11-78112745-C-T
• rs61995925
• NM_024079.5:c.803G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024079.5(ALG8):​c.803G>A​(p.Arg268Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,613,666 control chromosomes in the GnomAD database, including 330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (25 hom., cov: 32)
  • Exomes 𝑓: 0.019 (305 hom.)
• Consequence: ALG8 NM_024079.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.33
• Publications: 13 publications found

Genes affected

ALG8 (HGNC:23161): (ALG8 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the second glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation of proteins. Mutations in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ih). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ALG8 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• ALG8-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, G2P, Ambry Genetics
• polycystic liver disease 3 with or without kidney cysts

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.017484665).
• BP6: Variant 11-78112745-C-T is Benign according to our data. Variant chr11-78112745-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96093.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 = 0.0142 (2153/152146) while in subpopulation NFE AF = 0.0215 (1459/68000). AF 95% confidence interval is 0.0205. There are 25 homozygotes in GnomAd4. There are 972 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024079.5. 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
	ALG8	NM_024079.5	MANE Select	c.803G>A	p.Arg268Gln	missense	Exon 8 of 13	NP_076984.2	A0A024R5K5
	ALG8	NM_001425224.1		c.896G>A	p.Arg299Gln	missense	Exon 9 of 14	NP_001412153.1
	ALG8	NM_001425225.1		c.803G>A	p.Arg268Gln	missense	Exon 8 of 14	NP_001412154.1	H0YDD3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG8	ENST00000299626.10	TSL:1 MANE Select	c.803G>A	p.Arg268Gln	missense	Exon 8 of 13	ENSP00000299626.5	Q9BVK2-1
	ALG8	ENST00000679559.1		c.803G>A	p.Arg268Gln	missense	Exon 8 of 14	ENSP00000505433.1	A0A7P0T919
	ALG8	ENST00000532440.6	TSL:3	c.803G>A	p.Arg268Gln	missense	Exon 8 of 14	ENSP00000433429.2	H0YDD3

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2153 AN: 152028 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.00863

GnomAD2 exomes AF: 0.0140 AC: 3514 AN: 250846 AF XY: 0.0139

Gnomad AFR exome AF: 0.00364

Gnomad AMR exome AF: 0.00634

Gnomad ASJ exome AF: 0.0344

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0194 AC: 28408 AN: 1461520 Hom.: 305 Cov.: 31 AF XY: 0.0189 AC XY: 13767 AN XY: 727088

African (AFR) AF: 0.00323 AC: 108 AN: 33472

American (AMR) AF: 0.00696 AC: 311 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0359 AC: 939 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00237 AC: 204 AN: 86216

European-Finnish (FIN) AF: 0.0157 AC: 837 AN: 53372

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0225 AC: 24973 AN: 1111792

Other (OTH) AF: 0.0170 AC: 1029 AN: 60382

GnomAD4 genome AF: 0.0142 AC: 2153 AN: 152146 Hom.: 25 Cov.: 32 AF XY: 0.0131 AC XY: 972 AN XY: 74360

African (AFR) AF: 0.00486 AC: 202 AN: 41532

American (AMR) AF: 0.0100 AC: 153 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4810

European-Finnish (FIN) AF: 0.0176 AC: 186 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0215 AC: 1459 AN: 68000

Other (OTH) AF: 0.00854 AC: 18 AN: 2108

Alfa AF: 0.0194 Hom.: 125

Bravo AF: 0.0131

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0226 AC: 87

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0220 AC: 189

ExAC AF: 0.0137 AC: 1661

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0195

EpiControl AF: 0.0186

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	ALG8 congenital disorder of glycosylation (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.56
MPC		0.68
ClinPred		0.068	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.82
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs61995925; hg19: chr11-77823791;