13-52024711-TAAG-T

Variant names:

• chr13-52024711-TAAG-T
• rs1064794465
• NM_001004127.3:c.986_988delAGA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_001004127.3(ALG11):​c.986_988delAGA​(p.Lys329del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALG11 NM_001004127.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 4.71

Genes affected

ALG11 (HGNC:32456): (ALG11 alpha-1,2-mannosyltransferase) This gene encodes a GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase which is localized to the cytosolic side of the endoplasmic reticulum (ER) and catalyzes the transfer of the fourth and fifth mannose residue from GDP-mannose (GDP-Man) to Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol resulting in the production of Man5GlcNAc2-PP-dolichol. Mutations in this gene are associated with congenital disorder of glycosylation type Ip (CDGIP). This gene overlaps but is distinct from the UTP14, U3 small nucleolar ribonucleoprotein, homolog C (yeast) gene. A pseudogene of the GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase has been identified on chromosome 19. [provided by RefSeq, Aug 2010]

UTP14C (HGNC:20321): (UTP14C small subunit processome component) Predicted to be involved in several processes, including meiotic cell cycle; rRNA processing; and spermatogenesis. Located in cytosol and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001004127.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 13-52024711-TAAG-T is Pathogenic according to our data. Variant chr13-52024711-TAAG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420418.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG11	NM_001004127.3	c.986_988delAGA	p.Lys329del	disruptive_inframe_deletion	Exon 3 of 4	ENST00000521508.2	NP_001004127.2
UTP14C	NM_021645.6	c.-708_-706delAGA		5_prime_UTR_variant	Exon 1 of 2	ENST00000521776.2	NP_067677.4
ALG11	NR_036571.3	n.66-3603_66-3601delAGA		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG11	ENST00000521508.2	c.986_988delAGA	p.Lys329del	disruptive_inframe_deletion	Exon 3 of 4	1	NM_001004127.3	ENSP00000430236.1
UTP14C	ENST00000521776	c.-708_-706delAGA		5_prime_UTR_variant	Exon 1 of 2	1	NM_021645.6	ENSP00000428619.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Aug 29, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM4, PM2, PM3_Supporting -

Jan 26, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.986_988delAGA variant has not been reported previously as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. This variant causes an inframe deletion of a single amino acid residue,denoted p.Lys329del. This deletion occurs at a region that is not conserved; however, this variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.986_988delAGA variant is a strong candidate for a pathogenic variant. -

ALG11-congenital disorder of glycosylation Pathogenic:1

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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: rs1064794465; hg19: chr13-52598847;