rs17825668

Variant names:

• chr11-78104013-A-G
• rs17825668
• NM_024079.5:c.1316T>C

Variant summary

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

The NM_024079.5(ALG8):​c.1316T>C​(p.Ile439Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,505,436 control chromosomes in the GnomAD database, including 708 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (46 hom., cov: 33)
  • Exomes 𝑓: 0.029 (662 hom.)
• Consequence: ALG8 NM_024079.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.57
• Publications: 15 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00791803).
• BP6: Variant 11-78104013-A-G is Benign according to our data. Variant chr11-78104013-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166677.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 = 0.0213 (3243/152252) while in subpopulation NFE AF = 0.0334 (2274/67990). AF 95% confidence interval is 0.0323. There are 46 homozygotes in GnomAd4. There are 1511 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 AR,AD 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.1316T>C	p.Ile439Thr	missense	Exon 12 of 13	NP_076984.2	A0A024R5K5
	ALG8	NM_001425224.1		c.1409T>C	p.Ile470Thr	missense	Exon 13 of 14	NP_001412153.1
	ALG8	NM_001425225.1		c.1364T>C	p.Ile455Thr	missense	Exon 13 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.1316T>C	p.Ile439Thr	missense	Exon 12 of 13	ENSP00000299626.5	Q9BVK2-1
	ALG8	ENST00000679559.1		c.1316T>C	p.Ile439Thr	missense	Exon 12 of 14	ENSP00000505433.1	A0A7P0T919
	ALG8	ENST00000532440.6	TSL:3	c.1364T>C	p.Ile455Thr	missense	Exon 13 of 14	ENSP00000433429.2	H0YDD3

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3245 AN: 152134 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.00536

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00953

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0225 AC: 5505 AN: 245044 AF XY: 0.0233

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0348

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0344

Gnomad OTH exome AF: 0.0252

GnomAD4 exome AF: 0.0292 AC: 39464 AN: 1353184 Hom.: 662 Cov.: 24 AF XY: 0.0287 AC XY: 19463 AN XY: 677500

African (AFR) AF: 0.00630 AC: 197 AN: 31284

American (AMR) AF: 0.0171 AC: 748 AN: 43630

Ashkenazi Jewish (ASJ) AF: 0.0358 AC: 898 AN: 25104

East Asian (EAS) AF: 0.0000513 AC: 2 AN: 38978

South Asian (SAS) AF: 0.0111 AC: 913 AN: 82450

European-Finnish (FIN) AF: 0.0133 AC: 704 AN: 52826

Middle Eastern (MID) AF: 0.0333 AC: 185 AN: 5558

European-Non Finnish (NFE) AF: 0.0336 AC: 34156 AN: 1016772

Other (OTH) AF: 0.0294 AC: 1661 AN: 56582

GnomAD4 genome AF: 0.0213 AC: 3243 AN: 152252 Hom.: 46 Cov.: 33 AF XY: 0.0203 AC XY: 1511 AN XY: 74464

African (AFR) AF: 0.00534 AC: 222 AN: 41562

American (AMR) AF: 0.0219 AC: 335 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0374 AC: 130 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00933 AC: 45 AN: 4822

European-Finnish (FIN) AF: 0.0109 AC: 116 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0334 AC: 2274 AN: 67990

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0303 Hom.: 384

Bravo AF: 0.0222

TwinsUK AF: 0.0378 AC: 140

ALSPAC AF: 0.0314 AC: 121

ESP6500AA AF: 0.00485 AC: 21

ESP6500EA AF: 0.0366 AC: 311

ExAC AF: 0.0217 AC: 2628

Asia WGS AF: 0.00579 AC: 21 AN: 3470

EpiCase AF: 0.0398

EpiControl AF: 0.0408

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.045
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.27
Sift	Benign	0.039	D
Sift4G	Uncertain	0.050	T
Polyphen		0.083	B
Vest4		0.098
MPC		0.19
ClinPred		0.021	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.31
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs17825668; hg19: chr11-77815059; COSMIC: COSV108091538; COSMIC: COSV108091538;