rs4075331

Variant names:

• chr22-49909202-A-G
• rs4075331
• NM_024105.4:c.768+42T>C

Your query was ambiguous. Multiple possible variants found:

• chr22-49909202-A-G
• chr22-49909202-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024105.4(ALG12):​c.768+42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,586,880 control chromosomes in the GnomAD database, including 59,250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (13926 hom., cov: 33)
  • Exomes 𝑓: 0.23 (45324 hom.)
• Consequence: ALG12 NM_024105.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.16
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• ALG12-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 22-49909202-A-G is Benign according to our data. Variant chr22-49909202-A-G is described in ClinVar as Benign. ClinVar VariationId is 261688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG12	NM_024105.4	c.768+42T>C		intron_variant	Intron 6 of 9	ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2	c.768+42T>C		intron_variant	Intron 6 of 9		XP_016884425.1
ALG12	XM_017028937.2	c.768+42T>C		intron_variant	Intron 6 of 10		XP_016884426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG12	ENST00000330817.11	c.768+42T>C		intron_variant	Intron 6 of 9	1	NM_024105.4	ENSP00000333813.5
ALG12	ENST00000492791.1	n.297+42T>C		intron_variant	Intron 2 of 5	3		ENSP00000417387.1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54361 AN: 152008 Hom.: 13867 Cov.: 33

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.306

GnomAD2 exomes AF: 0.256 AC: 64121 AN: 250590 AF XY: 0.259

Gnomad AFR exome AF: 0.742

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.134

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.230 AC: 329325 AN: 1434754 Hom.: 45324 Cov.: 27 AF XY: 0.235 AC XY: 168042 AN XY: 715472

African (AFR) AF: 0.753 AC: 24866 AN: 33010

American (AMR) AF: 0.160 AC: 7154 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 7730 AN: 25972

East Asian (EAS) AF: 0.137 AC: 5431 AN: 39530

South Asian (SAS) AF: 0.427 AC: 36594 AN: 85800

European-Finnish (FIN) AF: 0.169 AC: 9008 AN: 53336

Middle Eastern (MID) AF: 0.323 AC: 1703 AN: 5266

European-Non Finnish (NFE) AF: 0.204 AC: 221587 AN: 1087738

Other (OTH) AF: 0.257 AC: 15252 AN: 59450

GnomAD4 genome AF: 0.358 AC: 54475 AN: 152126 Hom.: 13926 Cov.: 33 AF XY: 0.353 AC XY: 26291 AN XY: 74382

African (AFR) AF: 0.729 AC: 30262 AN: 41492

American (AMR) AF: 0.223 AC: 3411 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1055 AN: 3472

East Asian (EAS) AF: 0.145 AC: 746 AN: 5154

South Asian (SAS) AF: 0.412 AC: 1986 AN: 4822

European-Finnish (FIN) AF: 0.166 AC: 1759 AN: 10604

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14093 AN: 67976

Other (OTH) AF: 0.310 AC: 655 AN: 2112

Alfa AF: 0.299 Hom.: 1783

Bravo AF: 0.370

Asia WGS AF: 0.335 AC: 1168 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.069
DANN	Benign	0.36
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4075331; hg19: chr22-50302850; COSMIC: COSV58206590; COSMIC: COSV58206590;