NM_024740.2:c.694G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_024740.2(ALG9):ā€‹c.694G>Cā€‹(p.Ala232Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000445 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00034 ( 0 hom., cov: 32)
Exomes š‘“: 0.00046 ( 0 hom. )

Consequence

ALG9
NM_024740.2 missense

Scores

5
10
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 3.61
Variant links:
Genes affected
ALG9 (HGNC:15672): (ALG9 alpha-1,2-mannosyltransferase) This gene encodes an alpha-1,2-mannosyltransferase enzyme that functions in lipid-linked oligosaccharide assembly. Mutations in this gene result in congenital disorder of glycosylation type Il. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000341 (52/152282) while in subpopulation NFE AF= 0.00072 (49/68018). AF 95% confidence interval is 0.00056. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALG9NM_024740.2 linkc.694G>C p.Ala232Pro missense_variant Exon 6 of 15 ENST00000616540.5 NP_079016.2 Q9H6U8-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALG9ENST00000616540.5 linkc.694G>C p.Ala232Pro missense_variant Exon 6 of 15 1 NM_024740.2 ENSP00000482437.1 Q9H6U8-3
ENSG00000258529ENST00000622211.4 linkc.1393G>C p.Ala465Pro missense_variant Exon 10 of 19 2 ENSP00000482396.1 A0A087WZ62

Frequencies

GnomAD3 genomes
AF:
0.000342
AC:
52
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000720
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000289
AC:
72
AN:
249556
Hom.:
0
AF XY:
0.000281
AC XY:
38
AN XY:
135398
show subpopulations
Gnomad AFR exome
AF:
0.000129
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.000325
Gnomad NFE exome
AF:
0.000539
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000456
AC:
666
AN:
1461844
Hom.:
0
Cov.:
32
AF XY:
0.000440
AC XY:
320
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.000431
Gnomad4 NFE exome
AF:
0.000554
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000341
AC:
52
AN:
152282
Hom.:
0
Cov.:
32
AF XY:
0.000349
AC XY:
26
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000720
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000435
Hom.:
0
Bravo
AF:
0.000366
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000257
AC:
1
ESP6500EA
AF:
0.000481
AC:
4
ExAC
AF:
0.000273
AC:
33
EpiCase
AF:
0.000491
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Nov 05, 2018
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 31, 2013
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 06, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported in the heterozygous state in a patient with kidney and liver cysts in published literature (PMID: 31395617); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31395617, 27391121) -

ALG9 congenital disorder of glycosylation Uncertain:2
Jan 11, 2019
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 20, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 232 of the ALG9 protein (p.Ala232Pro). This variant is present in population databases (rs36111204, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of ALG9-related conditions (PMID: 27391121, 31395617). ClinVar contains an entry for this variant (Variation ID: 96135). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ALG9 function (PMID: 31395617). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Gillessen-Kaesbach-Nishimura syndrome;C2931006:ALG9 congenital disorder of glycosylation Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

See cases Benign:1
Dec 25, 2019
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PM2, BP1, BP4 -

Autosomal dominant polycystic liver disease Benign:1
May 21, 2019
Stefan Somlo Laboratory, Yale School of Medicine
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: research

Variant able to rescue ALG9 knockout effect on Polycystin-1 maturation in vitro -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Uncertain
0.032
T
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.46
T;.;.;.;.
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.97
D;D;D;D;D
M_CAP
Benign
0.039
D
MetaRNN
Uncertain
0.60
D;D;D;D;D
MetaSVM
Uncertain
0.022
D
MutationAssessor
Pathogenic
3.0
M;.;.;M;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-2.7
.;D;D;.;.
REVEL
Uncertain
0.40
Sift
Benign
0.047
.;D;D;.;.
Sift4G
Benign
0.077
T;T;T;T;T
Polyphen
0.98
D;.;.;D;.
Vest4
0.90
MVP
0.93
MPC
0.97
ClinPred
0.64
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.61
gMVP
0.92

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs36111204; hg19: chr11-111728332; API