rs759244819

Positions:

chr22-49904497-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024105.4(ALG12):c.1001del(p.Asn334ThrfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ALG12
NM_024105.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.30

Variant links:

Genes affected

ALG12 (HGNC:19358): (ALG12 alpha-1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 22 family. The encoded protein catalyzes the addition of the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP-Man(7)GlcNAc(2)) required for protein glycosylation. Mutations in this gene have been associated with congenital disorder of glycosylation type Ig (CDG-Ig)characterized by abnormal N-glycosylation. [provided by RefSeq, Jul 2008]

ALG12 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-49904497-GT-G is Pathogenic according to our data. Variant chr22-49904497-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALG12	NM_024105.4 linkuse as main transcript	c.1001del	p.Asn334ThrfsTer15	frameshift_variant	8/10	ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2 linkuse as main transcript	c.1001del	p.Asn334ThrfsTer15	frameshift_variant	8/10		XP_016884425.1
ALG12	XM_017028937.2 linkuse as main transcript	c.1001del	p.Asn334ThrfsTer15	frameshift_variant	8/11		XP_016884426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ALG12	ENST00000330817.11 linkuse as main transcript	c.1001del	p.Asn334ThrfsTer15	frameshift_variant	8/10	1	NM_024105.4	ENSP00000333813	P1
	ENST00000610245.1 linkuse as main transcript	n.2272del		non_coding_transcript_exon_variant	1/1
ALG12	ENST00000486602.1 linkuse as main transcript	c.207del	p.Asn70ThrfsTer15	frameshift_variant	2/4	3		ENSP00000420630
ALG12	ENST00000492791.1 linkuse as main transcript	c.524-114del		intron_variant, NMD_transcript_variant		3		ENSP00000417387

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000479

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

251142

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000246

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:

0.0000126

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000479

Bravo

AF:

0.0000416

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ALG12-congenital disorder of glycosylation

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2024	Variant summary: ALG12 c.1001delA (p.Asn334ThrfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.2e-05 in 251142 control chromosomes. c.1001delA has been reported in the literature in individuals affected with ALG12-Congenital Disorder Of Glycosylation (e.g. Murali_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25019053). ClinVar contains an entry for this variant (Variation ID: 242854). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Asn334Thrfs*15) in the ALG12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALG12 are known to be pathogenic (PMID: 15639192, 31481313). This variant is present in population databases (rs759244819, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of congenital disorders of glycosylation (PMID: 25019053, 31481313). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 242854). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Apr 01, 2014	This variant was found in trans with pathogenic variant NM_024105.3:c.117delG in an individual with congenital disorder of glycosylation type Ig. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Nov 07, 2019	This frameshifting variant in exon 8 of 10 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a compound heterozygous change in patients with Congenital disorder of glycosylation type Ig (PMID: 25019053). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0052% (13/251142) and thus is presumed to be rare. Based on the available evidence, the c.1001del (p.Asn334ThrfsTer15) variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 06, 2020	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2020

The alteration results in a premature stop codon: _x000D_ _x000D_ The c.1001delA (p.N334Tfs*15) alteration, located in exon 8 (coding exon 7) of the ALG12 gene, results from a deletion of one nucleotide at position 1001, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD) database, the ALG12 c.1001delA alteration was observed in <0.01% (13/251142) of total alleles studied, with a frequency of 0.03% (9/34584) in the Latino subpopulation. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration was reported with another frameshift alteration, c.117delG (p.Q40Rfs*34), in ALG12 in an infant with rhizomelic short stature, talipes equinovarus, platyspondyly, and joint dislocations (Murali, 2014). Tahata, et al. (2019) reported this alteration in trans with c.671C>T (p.T224M) in two affected brothers who only had cognitive impairment and coagulation defects. They also had a younger brother who died from a severe multisystem disease at age 18 months and was suspected of having congenital disorder of glycosylation. Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 24, 2023

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 31481313, 33144682, 25019053, 33413482) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over