NM_019109.5:c.1280T>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 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 VariationId is 1012177.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019109.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	NM_019109.5	MANE Select	c.1280T>G	p.Phe427Cys	missense	Exon 13 of 13	NP_061982.3
	EEF2KMT	NM_201400.4	MANE Select	c.*866A>C		3_prime_UTR	Exon 8 of 8	NP_958802.1	Q96G04-1
	ALG1	NM_001438123.1		c.1241T>G	p.Phe414Cys	missense	Exon 12 of 12	NP_001425052.1	A0A804HJL6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	ENST00000262374.10	TSL:1 MANE Select	c.1280T>G	p.Phe427Cys	missense	Exon 13 of 13	ENSP00000262374.5	Q9BT22-1
	ALG1	ENST00000588623.5	TSL:1	c.947T>G	p.Phe316Cys	missense	Exon 14 of 14	ENSP00000468118.1	Q9BT22-2
	EEF2KMT	ENST00000427587.9	TSL:1 MANE Select	c.*866A>C		3_prime_UTR	Exon 8 of 8	ENSP00000398502.3	Q96G04-1

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

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111750

Other (OTH) AF: 0.00 AC: 0 AN: 60110

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	ALG1-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.085	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	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

Other links and lift over

dbSNP: rs1957090242; hg19: chr16-5134767;