3-130091350-C-T

Variant names:

• chr3-130091350-C-T
• rs568221197
• NM_001136152.1:c.110C>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.110C>T​(p.Thr37Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000751 in 1,597,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: ALG1L2 NM_001136152.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.225

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=0.056136727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG1L2	NM_001136152.1	c.110C>T	p.Thr37Met	missense_variant	Exon 2 of 8	ENST00000425059.1	NP_001129624.1
LINC02014	NR_146710.1	n.249-230G>A		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG1L2	ENST00000425059.1	c.110C>T	p.Thr37Met	missense_variant	Exon 2 of 8	5	NM_001136152.1	ENSP00000479850.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000845 AC: 20 AN: 236632 Hom.: 0 AF XY: 0.0000696 AC XY: 9 AN XY: 129268

Gnomad AFR exome AF: 0.0000655

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000254

Gnomad NFE exome AF: 0.0000724

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000768 AC: 111 AN: 1445006 Hom.: 0 Cov.: 34 AF XY: 0.0000737 AC XY: 53 AN XY: 719264

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000308

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000992 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.110C>T (p.T37M) alteration is located in exon 2 (coding exon 2) of the ALG1L2 gene. This alteration results from a C to T substitution at nucleotide position 110, causing the threonine (T) at amino acid position 37 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	0.091
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	2.6
DANN	Benign	0.72
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.056	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.44	T
Sift4G	Benign	0.10	T
Polyphen		0.0090	B
Vest4		0.13
MVP		0.014
GERP RS		-0.83
Varity_R		0.024
gMVP		0.46

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: rs568221197; hg19: chr3-129810193; COSMIC: COSV101405968; COSMIC: COSV101405968;