chr11-111865258-G-A

Variant names:

• chr11-111865258-G-A
• rs45574638
• NM_024740.2:c.406-7C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_024740.2(ALG9):​c.406-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,548,022 control chromosomes in the GnomAD database, including 906 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (78 hom., cov: 33)
  • Exomes 𝑓: 0.033 (828 hom.)
• Consequence: ALG9 NM_024740.2 splice_region, intron
• Scores: Splicing: ADA: 0.00006998
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.852
• Publications: 3 publications found

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]

ALG9 Gene-Disease associations (from GenCC):

• ALG9-associated autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• ALG9-congenital disorder of glycosylation

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet
• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Gillessen-Kaesbach-Nishimura syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ENSG00000258529 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 11-111865258-G-A is Benign according to our data. Variant chr11-111865258-G-A is described in ClinVar as Benign. ClinVar VariationId is 96134.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 = 0.0252 (3831/152152) while in subpopulation NFE AF = 0.0362 (2461/67974). AF 95% confidence interval is 0.035. There are 78 homozygotes in GnomAd4. There are 1894 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 78 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024740.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG9	NM_024740.2	MANE Select	c.406-7C>T		splice_region intron	N/A	NP_079016.2
	ALG9	NM_001441203.1		c.406-7C>T		splice_region intron	N/A	NP_001428132.1
	ALG9	NM_001352417.1		c.406-7C>T		splice_region intron	N/A	NP_001339346.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG9	ENST00000616540.5	TSL:1 MANE Select	c.406-7C>T		splice_region intron	N/A	ENSP00000482437.1
	ENSG00000258529	ENST00000622211.4	TSL:2	c.1105-7C>T		splice_region intron	N/A	ENSP00000482396.1
	ALG9	ENST00000614444.4	TSL:1	c.406-7C>T		splice_region intron	N/A	ENSP00000484200.1

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3830 AN: 152034 Hom.: 78 Cov.: 33

Gnomad AFR AF: 0.00602

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0336

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.0399

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.0340

GnomAD2 exomes AF: 0.0251 AC: 3942 AN: 157232 AF XY: 0.0253

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.0208

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.000185

Gnomad FIN exome AF: 0.0351

Gnomad NFE exome AF: 0.0367

Gnomad OTH exome AF: 0.0263

GnomAD4 exome AF: 0.0326 AC: 45528 AN: 1395870 Hom.: 828 Cov.: 29 AF XY: 0.0319 AC XY: 21974 AN XY: 688562

African (AFR) AF: 0.00520 AC: 163 AN: 31342

American (AMR) AF: 0.0215 AC: 754 AN: 35140

Ashkenazi Jewish (ASJ) AF: 0.0255 AC: 639 AN: 25080

East Asian (EAS) AF: 0.0000841 AC: 3 AN: 35668

South Asian (SAS) AF: 0.0111 AC: 870 AN: 78474

European-Finnish (FIN) AF: 0.0323 AC: 1594 AN: 49384

Middle Eastern (MID) AF: 0.0180 AC: 102 AN: 5674

European-Non Finnish (NFE) AF: 0.0369 AC: 39715 AN: 1077160

Other (OTH) AF: 0.0291 AC: 1688 AN: 57948

GnomAD4 genome AF: 0.0252 AC: 3831 AN: 152152 Hom.: 78 Cov.: 33 AF XY: 0.0255 AC XY: 1894 AN XY: 74394

African (AFR) AF: 0.00600 AC: 249 AN: 41510

American (AMR) AF: 0.0335 AC: 513 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4828

European-Finnish (FIN) AF: 0.0399 AC: 422 AN: 10582

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

European-Non Finnish (NFE) AF: 0.0362 AC: 2461 AN: 67974

Other (OTH) AF: 0.0336 AC: 71 AN: 2112

Alfa AF: 0.0323 Hom.: 50

Bravo AF: 0.0242

Asia WGS AF: 0.00606 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

May 29, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

ALG9 congenital disorder of glycosylation Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.1
DANN	Benign	0.78
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000070
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.030		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: rs45574638; hg19: chr11-111735981;