NM_024079.5:c.896T>C

Variant names:

• chr11-78112652-A-G
• rs61995922
• NM_024079.5:c.896T>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.896T>C​(p.Ile299Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00113 in 1,613,828 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I299I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0058 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (9 hom.)
• Consequence: ALG8 NM_024079.5 missense, splice_region
• Scores: Splicing: ADA: 0.0002569
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.43
• Publications: 6 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=0.0097923875).
• BP6: Variant 11-78112652-A-G is Benign according to our data. Variant chr11-78112652-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 306218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00577 (879/152302) while in subpopulation AFR AF = 0.0201 (834/41564). AF 95% confidence interval is 0.0189. There are 8 homozygotes in GnomAd4. There are 432 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.896T>C	p.Ile299Thr	missense splice_region	Exon 8 of 13	NP_076984.2	A0A024R5K5
	ALG8	NM_001425224.1		c.989T>C	p.Ile330Thr	missense splice_region	Exon 9 of 14	NP_001412153.1
	ALG8	NM_001425225.1		c.896T>C	p.Ile299Thr	missense splice_region	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.896T>C	p.Ile299Thr	missense splice_region	Exon 8 of 13	ENSP00000299626.5	Q9BVK2-1
	ALG8	ENST00000530454.6	TSL:5	c.896T>C	p.Ile299Thr	missense	Exon 8 of 8	ENSP00000434660.2	E9PP96
	ALG8	ENST00000679559.1		c.896T>C	p.Ile299Thr	missense splice_region	Exon 8 of 14	ENSP00000505433.1	A0A7P0T919

Frequencies

GnomAD3 genomes AF: 0.00576 AC: 877 AN: 152184 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00162 AC: 408 AN: 251420 AF XY: 0.00128

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000647 AC: 946 AN: 1461526 Hom.: 9 Cov.: 31 AF XY: 0.000576 AC XY: 419 AN XY: 727062

African (AFR) AF: 0.0216 AC: 723 AN: 33460

American (AMR) AF: 0.00143 AC: 64 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

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

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111772

Other (OTH) AF: 0.00137 AC: 83 AN: 60368

GnomAD4 genome AF: 0.00577 AC: 879 AN: 152302 Hom.: 8 Cov.: 32 AF XY: 0.00580 AC XY: 432 AN XY: 74472

African (AFR) AF: 0.0201 AC: 834 AN: 41564

American (AMR) AF: 0.00183 AC: 28 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68026

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00233 Hom.: 6

Bravo AF: 0.00687

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00207 AC: 251

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.4
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.022	D
Sift4G	Benign	0.16	T
Polyphen		0.0010	B
Vest4		0.29
MVP		0.97
MPC		0.19
ClinPred		0.039	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.46
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.050
SpliceAI score (max)		0.020		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: rs61995922; hg19: chr11-77823698;