16-5077459-T-G

Variant names:

• chr16-5077459-T-G
• rs112668461
• NM_019109.5:c.554T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019109.5(ALG1):​c.554T>G​(p.Phe185Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,614,118 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (41 hom.)
• Consequence: ALG1 NM_019109.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.81
• Publications: 5 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]

ALG1 Gene-Disease associations (from GenCC):

• ALG1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008822262).
• BP6: Variant 16-5077459-T-G is Benign according to our data. Variant chr16-5077459-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 384255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0126 (1912/152258) while in subpopulation AFR AF = 0.0432 (1797/41550). AF 95% confidence interval is 0.0416. There are 40 homozygotes in GnomAd4. There are 915 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

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.554T>G	p.Phe185Cys	missense	Exon 5 of 13	NP_061982.3
	ALG1	NM_001438123.1		c.554T>G	p.Phe185Cys	missense	Exon 5 of 12	NP_001425052.1	A0A804HJL6
	ALG1	NM_001330504.2		c.221T>G	p.Phe74Cys	missense	Exon 5 of 13	NP_001317433.1	Q9BT22-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	ENST00000262374.10	TSL:1 MANE Select	c.554T>G	p.Phe185Cys	missense	Exon 5 of 13	ENSP00000262374.5	Q9BT22-1
	ALG1	ENST00000588623.5	TSL:1	c.221T>G	p.Phe74Cys	missense	Exon 6 of 14	ENSP00000468118.1	Q9BT22-2
	ALG1	ENST00000591822.5	TSL:1	n.*455T>G		non_coding_transcript_exon	Exon 5 of 13	ENSP00000467865.1	K7EQK1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1902 AN: 152140 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.00337 AC: 848 AN: 251484 AF XY: 0.00258

Gnomad AFR exome AF: 0.0437

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00145 AC: 2123 AN: 1461860 Hom.: 41 Cov.: 32 AF XY: 0.00128 AC XY: 934 AN XY: 727232

African (AFR) AF: 0.0463 AC: 1549 AN: 33478

American (AMR) AF: 0.00286 AC: 128 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.000174 AC: 194 AN: 1111990

Other (OTH) AF: 0.00369 AC: 223 AN: 60394

GnomAD4 genome AF: 0.0126 AC: 1912 AN: 152258 Hom.: 40 Cov.: 33 AF XY: 0.0123 AC XY: 915 AN XY: 74458

African (AFR) AF: 0.0432 AC: 1797 AN: 41550

American (AMR) AF: 0.00445 AC: 68 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68020

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.00483 Hom.: 33

Bravo AF: 0.0146

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0407 AC: 179

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00429 AC: 521

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	ALG1-congenital disorder of glycosylation (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.8
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.24
Sift	Benign	0.11	T
Sift4G	Benign	0.11	T
Polyphen		0.074	B
Vest4		0.48
MVP		0.85
MPC		0.057
ClinPred		0.030	T
GERP RS		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.81
Mutation Taster		=92/8	polymorphism

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: rs112668461; hg19: chr16-5127460;