rs17113312

chr11-111853674-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024740.2(ALG9):c.764C>T(p.Ser255Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,613,976 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S255S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (37 hom.)
• Consequence: ALG9 NM_024740.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.60

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008018106).
• BP6: Variant 11-111853674-G-A is Benign according to our data. Variant chr11-111853674-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 96136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0113 (1718/152190) while in subpopulation AFR AF= 0.0397 (1649/41516). AF 95% confidence interval is 0.0381. There are 47 homozygotes in gnomad4. There are 817 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG9	NM_024740.2	c.764C>T	p.Ser255Leu	missense_variant	7/15	ENST00000616540.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG9	ENST00000616540.5	c.764C>T	p.Ser255Leu	missense_variant	7/15	1	NM_024740.2

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1714 AN: 152072 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0397

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00274 AC: 683 AN: 249278 Hom.: 10 AF XY: 0.00210 AC XY: 284 AN XY: 135248

Gnomad AFR exome AF: 0.0396

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00118 AC: 1719 AN: 1461786 Hom.: 37 Cov.: 31 AF XY: 0.00100 AC XY: 729 AN XY: 727194

Gnomad4 AFR exome AF: 0.0437

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.0113 AC: 1718 AN: 152190 Hom.: 47 Cov.: 32 AF XY: 0.0110 AC XY: 817 AN XY: 74402

Gnomad4 AFR AF: 0.0397

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00207 Hom.: 9

Bravo AF: 0.0131

ESP6500AA AF: 0.0383 AC: 141

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00347 AC: 419

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 28, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 02, 2018	- -

Gillessen-Kaesbach-Nishimura syndrome;C2931006:ALG9 congenital disorder of glycosylation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 12, 2021

- -

ALG9 congenital disorder of glycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
MetaRNN	Benign	0.0080	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.81	P;.;.;P;.
Vest4		0.45
MVP		0.80
MPC		0.28
ClinPred		0.012	T
GERP RS		5.9
Varity_R		0.23
gMVP		0.89

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: rs17113312; hg19: chr11-111724397;