Genetic Variant ALG5:c.-34+352_-34+353insT (chr13-37000344-C-CA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The ENST00000681893.1(ALG5):c.-34+352_-34+353insT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 0)

Exomes 𝑓: 0.029 ( 0 hom. )

Consequence

ALG5
ENST00000681893.1 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.208

Publications

0 publications found

Variant links:

Genes affected

ALG5 (HGNC:20266): (ALG5 dolichyl-phosphate beta-glucosyltransferase) This gene encodes a member of the glycosyltransferase 2 family. The encoded protein participates in glucosylation of the oligomannose core in N-linked glycosylation of proteins. The addition of glucose residues to the oligomannose core is necessary to ensure substrate recognition, and therefore, effectual transfer of the oligomannose core to the nascent glycoproteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

ALG5 links:

EXOSC8 (HGNC:17035): (exosome component 8) This gene encodes a 3'-5' exoribonuclease that specifically interacts with mRNAs containing AU-rich elements. The encoded protein is part of the exosome complex that is important for the degradation of numerous RNA species. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Mar 2009]

EXOSC8 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia, type 1C
Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
pontocerebellar hypoplasia type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EXOSC8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000334 (33/98872) while in subpopulation AFR AF = 0.000617 (17/27562). AF 95% confidence interval is 0.000392. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 33 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000681893.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ALG5	ENST00000681893.1		c.-34+352_-34+353insT	intron	N/A	ENSP00000506235.1	A0A7P0T901
EXOSC8	ENST00000489088.5	TSL:3	n.379+1150_379+1151insA	intron	N/A
ALG5	ENST00000680949.1		n.-34+352_-34+353insT	intron	N/A	ENSP00000506156.1	A0A7P0Z4I2

Frequencies

GnomAD3 genomes

AF:

0.000334

AC:

AN:

98894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000618

Gnomad AMI

AF:

0.00164

Gnomad AMR

AF:

0.000101

Gnomad ASJ

AF:

0.000406

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000431

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000237

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0286

AC:

AN:

1468

Hom.:

Cov.:

AF XY:

0.0262

AC XY:

AN XY:

954

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0357

AC:

AN:

American (AMR)

AF:

0.0556

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.0172

AC:

AN:

640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0338

AC:

AN:

622

Other (OTH)

AF:

0.0556

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.312

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:

0.000334

AC:

AN:

98872

Hom.:

Cov.:

AF XY:

0.000320

AC XY:

AN XY:

46892

show subpopulations

African (AFR)

AF:

0.000617

AC:

AN:

27562

American (AMR)

AF:

0.000101

AC:

AN:

9874

Ashkenazi Jewish (ASJ)

AF:

0.000406

AC:

AN:

2466

East Asian (EAS)

AF:

0.00

AC:

AN:

3268

South Asian (SAS)

AF:

0.00

AC:

AN:

2642

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

4636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.000237

AC:

AN:

46326

Other (OTH)

AF:

0.00

AC:

AN:

1280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00

Hom.:

767

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.21

Splicing

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

Publications

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13-37000344-CAAAAAAAAAAAA-CAAAAAAAAAAAAA

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