rs78243190

Variant names:

• chr11-111782974-A-G
• rs78243190
• NM_024740.2:c.*3423T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_024740.2(ALG9):​c.*3423T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 152,358 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0017 (1 hom., cov: 32)
• Consequence: ALG9 NM_024740.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36
• Publications: 1 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: G2P, Ambry Genetics, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant polycystic kidney disease

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

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00167 (254/152358) while in subpopulation AFR AF = 0.00599 (249/41586). AF 95% confidence interval is 0.00538. There are 1 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG9	NM_024740.2	MANE Select	c.*3423T>C		3_prime_UTR	Exon 15 of 15	NP_079016.2	Q9H6U8-3
	ALG9	NM_001441203.1		c.*3083T>C		3_prime_UTR	Exon 16 of 16	NP_001428132.1
	ALG9	NM_001352417.1		c.*3083T>C		3_prime_UTR	Exon 16 of 16	NP_001339346.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG9	ENST00000616540.5	TSL:1 MANE Select	c.*3423T>C		3_prime_UTR	Exon 15 of 15	ENSP00000482437.1	Q9H6U8-3
	ALG9	ENST00000532425.6	TSL:3	c.*3083T>C		3_prime_UTR	Exon 6 of 6	ENSP00000432442.2	H0YCW6

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 254 AN: 152240 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.00167 AC: 254 AN: 152358 Hom.: 1 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74510

African (AFR) AF: 0.00599 AC: 249 AN: 41586

American (AMR) AF: 0.000327 AC: 5 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000747 Hom.: 0

Bravo AF: 0.00174

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	ALG9 congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.4
DANN	Benign	0.74
PhyloP100		1.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs78243190; hg19: chr11-111653698;