16-5084766-T-G

Variant names:

• chr16-5084766-T-G
• rs1957090242
• NM_019109.5:c.1280T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_019109.5(ALG1):​c.1280T>G​(p.Phe427Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,444,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. F427F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ALG1 NM_019109.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.69

Genes affected

ALG1 (HGNC:18294): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase) The enzyme encoded by this gene catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides. This gene is mutated in congenital disorder of glycosylation type Ik. [provided by RefSeq, Dec 2008]

EEF2KMT (HGNC:32221): (eukaryotic elongation factor 2 lysine methyltransferase) Enables protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine trimethylation. Located in cytoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836
• PP5: Variant 16-5084766-T-G is Pathogenic according to our data. Variant chr16-5084766-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1012177.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG1	NM_019109.5	c.1280T>G	p.Phe427Cys	missense_variant	Exon 13 of 13	ENST00000262374.10	NP_061982.3
EEF2KMT	NM_201400.4	c.*866A>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000427587.9	NP_958802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10	c.1280T>G	p.Phe427Cys	missense_variant	Exon 13 of 13	1	NM_019109.5	ENSP00000262374.5
EEF2KMT	ENST00000427587	c.*866A>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_201400.4	ENSP00000398502.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444134 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718808

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

ALG1-congenital disorder of glycosylation Pathogenic:1

Mar 05, 2021

Institute of Human Genetics, Cologne University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

PM2_supporting, PP3, PM3_strong (the variant was found compound-heterozygous with p.S258L in the patient (1 point) and was found in homozygous state in two affected siblings of an unrelated family (additional 1 point), personal communication Johannes Gutenberg University, Mainz) , according to ClinGen recommendation v1.0 for PM3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	.;D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.085	D
MutationAssessor	Pathogenic	3.0	.;M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.3	.;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.83
MutPred		0.49		.;Loss of stability (P = 0.0829);.;
MVP		0.92
MPC		2.1
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.95
gMVP		0.79

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: rs1957090242; hg19: chr16-5134767;