11-78101103-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024079.5(ALG8):c.1442C>T(p.Thr481Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T481T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALG8 NM_024079.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.66

Genes affected

ALG8 (HGNC:23161): (ALG8 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the second glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation of proteins. Mutations in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ih). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27371743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG8	NM_024079.5	c.1442C>T	p.Thr481Ile	missense_variant	13/13	ENST00000299626.10
ALG8	XM_005274247.4	c.1415C>T	p.Thr472Ile	missense_variant	13/13
ALG8	NM_001007027.3	c.*113C>T		3_prime_UTR_variant	14/14
ALG8	XR_950044.4	n.1340C>T		non_coding_transcript_exon_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG8	ENST00000299626.10	c.1442C>T	p.Thr481Ile	missense_variant	13/13	1	NM_024079.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.1442C>T (p.T481I) alteration is located in exon 13 (coding exon 13) of the ALG8 gene. This alteration results from a C to T substitution at nucleotide position 1442, causing the threonine (T) at amino acid position 481 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	18
Dann	Benign	0.90
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.94	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.54	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.55	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.067	B;.
Vest4		0.31
MutPred		0.51		Loss of glycosylation at T481 (P = 0.0712);.;
MVP		0.90
MPC		0.16
ClinPred		0.49	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.27

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: rs1859775779; hg19: chr11-77812149;