rs45516107

Positions:

• chr11-111837557-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_024740.2(ALG9):​c.1383C>T​(p.Thr461=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00884 in 1,614,154 control chromosomes in the GnomAD database, including 85 homozygotes. 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 0.0053 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (83 hom.)
• Consequence: ALG9 NM_024740.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.190

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 11-111837557-G-A is Benign according to our data. Variant chr11-111837557-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 380142.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00526 (801/152302) while in subpopulation NFE AF= 0.00936 (637/68030). AF 95% confidence interval is 0.00876. There are 2 homozygotes in gnomad4. There are 364 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG9	NM_024740.2	c.1383C>T	p.Thr461=	synonymous_variant	12/15	ENST00000616540.5	NP_079016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG9	ENST00000616540.5	c.1383C>T	p.Thr461=	synonymous_variant	12/15	1	NM_024740.2	ENSP00000482437

Frequencies

GnomAD3 genomes AF: 0.00526 AC: 801 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00936

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00535 AC: 1336 AN: 249528 Hom.: 5 AF XY: 0.00552 AC XY: 747 AN XY: 135384

Gnomad AFR exome AF: 0.00200

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00209

Gnomad NFE exome AF: 0.00959

Gnomad OTH exome AF: 0.00577

GnomAD4 exome AF: 0.00921 AC: 13465 AN: 1461852 Hom.: 83 Cov.: 32 AF XY: 0.00894 AC XY: 6499 AN XY: 727232

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00248

Gnomad4 FIN exome AF: 0.00234

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.00745

GnomAD4 genome AF: 0.00526 AC: 801 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00489 AC XY: 364 AN XY: 74480

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00936

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00824 Hom.: 15

Bravo AF: 0.00569

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.00800

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ALG9: BP4, BP7, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 14, 2022	- -

ALG9 congenital disorder of glycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

- -

ALG9-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.1
DANN	Benign	0.77

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

Other links and lift over

dbSNP: rs45516107; hg19: chr11-111708280; COSMIC: COSV67644180; COSMIC: COSV67644180;