rs45574638

Positions:

• chr11-111865258-G-A

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006998
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.852

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 78 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG9	NM_024740.2	c.406-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000616540.5	NP_079016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG9	ENST00000616540.5	c.406-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_024740.2	ENSP00000482437

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

GnomAD3 exomes AF: 0.0251 AC: 3942 AN: 157232 Hom.: 59 AF XY: 0.0253 AC XY: 2095 AN XY: 82680

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 SAS exome AF: 0.00937

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

Gnomad4 AFR exome AF: 0.00520

Gnomad4 AMR exome AF: 0.0215

Gnomad4 ASJ exome AF: 0.0255

Gnomad4 EAS exome AF: 0.0000841

Gnomad4 SAS exome AF: 0.0111

Gnomad4 FIN exome AF: 0.0323

Gnomad4 NFE exome AF: 0.0369

Gnomad4 OTH exome AF: 0.0291

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

Gnomad4 AFR AF: 0.00600

Gnomad4 AMR AF: 0.0335

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.0399

Gnomad4 NFE AF: 0.0362

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0318 Hom.: 36

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 29, 2013	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

ALG9 congenital disorder of glycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.1
DANN	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs45574638; hg19: chr11-111735981;