rs1057518724

Positions:

• chr1-63419370-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_013339.4(ALG6):​c.988G>T​(p.Val330Phe) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALG6 NM_013339.4 missense, splice_region
• Scores: Splicing: ADA: 0.9984
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 6.40

Genes affected

ALG6 (HGNC:23157): (ALG6 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the first glucose residue to the growing lipid-linked oligosaccharide precursor of N-linked glycosylation. Mutations in this gene are associated with congenital disorders of glycosylation type Ic. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity ALG6_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_013339.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG6	NM_013339.4	c.988G>T	p.Val330Phe	missense_variant, splice_region_variant	12/15	ENST00000263440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG6	ENST00000263440.6	c.988G>T	p.Val330Phe	missense_variant, splice_region_variant	12/15	5	NM_013339.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456212 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724362

Gnomad4 AFR exome AF: 0.00

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

ALG6-congenital disorder of glycosylation 1C Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Baylor Genetics	May 01, 2016	Our laboratory reported dual molecular diagnoses in ALG6 (NM_013339.3:c.257+5G>A; NM_013339.3:c.988G>T; in trans) and SHOX (NM_000451.3:c.517C>T) in an individual with mild hypotonia, poor feeding, congenital heart disease (VSD, PFO, PDA), seizure disorder, dysmorphic facies, small chest wall, bowed lower legs, apparently short upper extremities, shallow sacral dimple, small for gestational age and a history of prematurity and intrauterine growth restriction. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 06, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D;.
Sift4G	Benign	0.28	T;.
Vest4		0.80
MVP		0.87
MPC		0.60
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.61
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.57		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057518724; hg19: chr1-63885041;