rs886111105

Variant names:

• chr4-118105095-T-G
• rs886111105
• NM_004784.3:c.1059T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004784.3(NDST3):​c.1059T>G​(p.Phe353Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,304 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 Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: NDST3 NM_004784.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.897
• Publications: 0 publications found

Genes affected

NDST3 (HGNC:7682): (N-deacetylase and N-sulfotransferase 3) This gene encodes a member of the heparan sulfate/heparin GlcNAc N-deacetylase/ N-sulfotransferase family. The encoded enzyme is a type II transmembrane protein that resides in the Golgi apparatus. This monomeric bifunctional enzyme catalyzes the N-deacetylation and N-sulfation of N-acetylglucosamine residues in heparan sulfate and heparin, which are the initial chemical modifications required for the biosynthesis of the functional oligosaccharide sequences that define the specific ligand binding activities of heparan sulfate and heparin. [provided by RefSeq, Nov 2008]

ENSG00000297398 (HGNC:58877):

LOC107986307 (HGNC:):

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, 0.937

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004784.3. 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
	NDST3	NM_004784.3	MANE Select	c.1059T>G	p.Phe353Leu	missense	Exon 3 of 14	NP_004775.1	O95803-1
	NDST3	NR_146513.2		n.1804T>G		non_coding_transcript_exon	Exon 3 of 14
	NDST3	NR_146514.2		n.1321T>G		non_coding_transcript_exon	Exon 3 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDST3	ENST00000296499.6	TSL:1 MANE Select	c.1059T>G	p.Phe353Leu	missense	Exon 3 of 14	ENSP00000296499.5	O95803-1
	NDST3	ENST00000852871.1		c.1059T>G	p.Phe353Leu	missense	Exon 3 of 14	ENSP00000522930.1
	ENSG00000297398	ENST00000747715.1		n.689-17051A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460148 Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9 AN XY: 726506

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1110606

Other (OTH) AF: 0.00 AC: 0 AN: 60328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000607818), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.90
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.82		Gain of sheet (P = 0.0827)
MVP		0.78
MPC		1.4
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.61
gMVP		0.71
Mutation Taster		=50/50

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: rs886111105; hg19: chr4-119026250;