16-5084751-T-C

Variant names:

• chr16-5084751-T-C
• NM_019109.5:c.1265T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019109.5(ALG1):​c.1265T>C​(p.Met422Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALG1 NM_019109.5 missense, splice_region
• Scores: Splicing: ADA: 0.00003150
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15301096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG1	NM_019109.5	c.1265T>C	p.Met422Thr	missense_variant, splice_region_variant	Exon 13 of 13	ENST00000262374.10	NP_061982.3
EEF2KMT	NM_201400.4	c.*881A>G		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.1265T>C	p.Met422Thr	missense_variant, splice_region_variant	Exon 13 of 13	1	NM_019109.5	ENSP00000262374.5
EEF2KMT	ENST00000427587	c.*881A>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_201400.4	ENSP00000398502.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

ALG1-congenital disorder of glycosylation Uncertain:1

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	14
DANN	Benign	0.67
DEOGEN2	Benign	0.11	.;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.65	.;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.14	.;N;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.28	.;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.59	.;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0020	.;B;.
Vest4		0.16
MutPred		0.37		.;Loss of catalytic residue at M422 (P = 0.0573);.;
MVP		0.81
MPC		1.4
ClinPred		0.063	T
GERP RS		2.7
Varity_R		0.039
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.014
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-5134752;