rs61995921

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_001425234.1(ALG8):c.-14A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

ALG8
NM_001425234.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 1.27

Publications

3 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
polycystic liver disease 3 with or without kidney cysts
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ALG8 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001425234.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012532502).

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000133 (195/1461860) while in subpopulation AFR AF = 0.0043 (144/33480). AF 95% confidence interval is 0.00373. There are 0 homozygotes in GnomAdExome4. There are 87 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001425234.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG8	NM_024079.5	MANE Select	c.251A>G	p.Tyr84Cys	missense	Exon 3 of 13	NP_076984.2	A0A024R5K5
ALG8	NM_001425234.1		c.-14A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	NP_001412163.1	E9PR58
ALG8	NM_001425239.1		c.-14A>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_001412168.1	A0A7P0TAA8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG8	ENST00000299626.10	TSL:1 MANE Select	c.251A>G	p.Tyr84Cys	missense	Exon 3 of 13	ENSP00000299626.5	Q9BVK2-1
ALG8	ENST00000532050.5	TSL:1	n.251A>G		non_coding_transcript_exon	Exon 3 of 8	ENSP00000437199.1	E9PNE2
ALG8	ENST00000681699.1		c.-14A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 14	ENSP00000504969.1	A0A7P0T810

Frequencies

GnomAD3 genomes

AF:

0.000887

AC:

135

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00311

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000298

AC:

AN:

251462

AF XY:

0.000206

show subpopulations

Gnomad AFR exome

AF:

0.00400

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000133

AC:

195

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00430

AC:

144

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111994

Other (OTH)

AF:

0.000348

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000887

AC:

135

AN:

152262

Hom.:

Cov.:

AF XY:

0.000940

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00310

AC:

129

AN:

41548

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000410

Hom.:

Bravo

AF:

0.00119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

ALG8 congenital disorder of glycosylation (3)

not provided (2)

ALG8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Benign

-0.071

Eigen_PC

Benign

0.039

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.052

MutationAssessor

Uncertain

2.7

PhyloP100

1.3

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.53

Sift

Benign

0.057

Sift4G

Benign

0.071

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.39

Mutation Taster

=61/39

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over