16-5071857-C-A

Position:

• chr16-5071857-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019109.5(ALG1):​c.8C>A​(p.Ala3Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,604,626 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (11 hom.)
• Consequence: ALG1 NM_019109.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.47

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]

ALG1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061694384).
• BP6: Variant 16-5071857-C-A is Benign according to our data. Variant chr16-5071857-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1669865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5071857-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00023 (35/152366) while in subpopulation SAS AF= 0.00621 (30/4834). AF 95% confidence interval is 0.00447. There are 1 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG1	NM_019109.5	c.8C>A	p.Ala3Asp	missense_variant	1/13	ENST00000262374.10	NP_061982.3
ALG1	XM_017023457.3	c.8C>A	p.Ala3Asp	missense_variant	1/12		XP_016878946.1
ALG1	XR_007064892.1	n.15C>A		non_coding_transcript_exon_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10	c.8C>A	p.Ala3Asp	missense_variant	1/13	1	NM_019109.5	ENSP00000262374.5

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152250 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00599

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000958 AC: 223 AN: 232826 Hom.: 3 AF XY: 0.00127 AC XY: 162 AN XY: 127816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.000922

Gnomad EAS exome AF: 0.0000561

Gnomad SAS exome AF: 0.00688

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000385

Gnomad OTH exome AF: 0.000345

GnomAD4 exome AF: 0.000421 AC: 611 AN: 1452260 Hom.: 11 Cov.: 31 AF XY: 0.000606 AC XY: 438 AN XY: 722670

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.000691

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00625

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.000383

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152366 Hom.: 1 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74514

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000984 AC: 119

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ALG1-congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 28, 2021	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

ALG1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.065	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.35	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.0062	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.84	D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.40
Sift	Benign	0.26	T;.
Sift4G	Uncertain	0.054	T;D
Polyphen		0.51	P;.
Vest4		0.73
MVP		0.81
MPC		0.080
ClinPred		0.044	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.76

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: rs559805054; hg19: chr16-5121858;