9-99217420-T-TA

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_033087.4(ALG2):c.*513_*514insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 453,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: ALG2 NM_033087.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0750

Genes affected

ALG2 (HGNC:23159): (ALG2 alpha-1,3/1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 1 family. The encoded protein acts as an alpha 1,3 mannosyltransferase, mannosylating Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate. Defects in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ii). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000316 (48/152026) while in subpopulation SAS AF= 0.00851 (41/4818). AF 95% confidence interval is 0.00645. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG2	NM_033087.4	c.*513_*514insT		3_prime_UTR_variant	2/2	ENST00000476832.2
ALG2	XM_047423996.1	c.*513_*514insT		3_prime_UTR_variant	2/2
ALG2	NR_024532.2	n.1971_1972insT		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG2	ENST00000476832.2	c.*513_*514insT		3_prime_UTR_variant	2/2	1	NM_033087.4	P1
ALG2	ENST00000319033.7	c.*513_*514insT		3_prime_UTR_variant	2/2	1
ALG2	ENST00000238477.5	c.*1506_*1507insT		3_prime_UTR_variant, NMD_transcript_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 151908 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00120 AC: 159 AN: 132878 Hom.: 0 AF XY: 0.00181 AC XY: 131 AN XY: 72560

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000822

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00684

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000577

Gnomad OTH exome AF: 0.000247

GnomAD4 exome AF: 0.00127 AC: 383 AN: 301812 Hom.: 0 Cov.: 0 AF XY: 0.00185 AC XY: 318 AN XY: 172000

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000733

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000109

Gnomad4 SAS exome AF: 0.00607

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.000641

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152026 Hom.: 0 Cov.: 33 AF XY: 0.000484 AC XY: 36 AN XY: 74336

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00851

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000907

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs544873504; hg19: chr9-101979702;