3-130092172-C-T

Variant names:

• chr3-130092172-C-T
• rs183887858
• NM_001136152.1:c.203C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001136152.1(ALG1L2):​c.203C>T​(p.Thr68Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,612,922 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: ALG1L2 NM_001136152.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.315

Genes affected

ALG1L2 (HGNC:37258): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase like 2) Predicted to enable mannosyltransferase activity. Predicted to be involved in protein glycosylation. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

LINC02014 (HGNC:52849): (long intergenic non-protein coding RNA 2014)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0050107837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG1L2	NM_001136152.1	c.203C>T	p.Thr68Met	missense_variant	Exon 3 of 8	ENST00000425059.1	NP_001129624.1
LINC02014	NR_146710.1	n.158-305G>A		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG1L2	ENST00000425059.1	c.203C>T	p.Thr68Met	missense_variant	Exon 3 of 8	5	NM_001136152.1	ENSP00000479850.1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000613 AC: 152 AN: 248050 Hom.: 0 AF XY: 0.000601 AC XY: 81 AN XY: 134788

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.00820

Gnomad EAS exome AF: 0.00104

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.000990

GnomAD4 exome AF: 0.000325 AC: 475 AN: 1460600 Hom.: 1 Cov.: 30 AF XY: 0.000343 AC XY: 249 AN XY: 726610

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00812

Gnomad4 EAS exome AF: 0.00111

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000746

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74478

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.000510

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.000503 AC: 61

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.203C>T (p.T68M) alteration is located in exon 3 (coding exon 3) of the ALG1L2 gene. This alteration results from a C to T substitution at nucleotide position 203, causing the threonine (T) at amino acid position 68 to be replaced by a methionine (M). 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	0.079
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.0
DANN	Benign	0.81
DEOGEN2	Benign	0.010	T
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0050	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.58	T
Sift4G	Benign	0.31	T
Polyphen		0.27	B
Vest4		0.16
MVP		0.014
GERP RS		-2.4
Varity_R		0.020
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs183887858; hg19: chr3-129811015; COSMIC: COSV70649254; COSMIC: COSV70649254;