4-114827915-A-C

Position:

• chr4-114827915-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022569.3(NDST4):​c.2520T>G​(p.Asn840Lys) variant causes a missense 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDST4 NM_022569.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.135

Genes affected

NDST4 (HGNC:20779): (N-deacetylase and N-sulfotransferase 4) Predicted to enable [heparan sulfate]-glucosamine N-sulfotransferase activity and deacetylase activity. Predicted to be involved in heparan sulfate proteoglycan biosynthetic process, polysaccharide chain biosynthetic process. Predicted to be located in Golgi membrane. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062228978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDST4	NM_022569.3	c.2520T>G	p.Asn840Lys	missense_variant	14/14	ENST00000264363.7	NP_072091.1
NDST4	XM_017008545.3	c.1383T>G	p.Asn461Lys	missense_variant	13/13		XP_016864034.1
NDST4	XM_017008546.2	c.1383T>G	p.Asn461Lys	missense_variant	12/12		XP_016864035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDST4	ENST00000264363.7	c.2520T>G	p.Asn840Lys	missense_variant	14/14	1	NM_022569.3	ENSP00000264363.2
NDST4	ENST00000504854.1	n.*371T>G		non_coding_transcript_exon_variant	13/13	1		ENSP00000423218.1
NDST4	ENST00000504854.1	n.*371T>G		3_prime_UTR_variant	13/13	1		ENSP00000423218.1
NDST4	ENST00000613194	c.*371T>G		3_prime_UTR_variant	15/15	5		ENSP00000483949.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.2520T>G (p.N840K) alteration is located in exon 14 (coding exon 13) of the NDST4 gene. This alteration results from a T to G substitution at nucleotide position 2520, causing the asparagine (N) at amino acid position 840 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.041
Sift	Benign	0.74	T
Sift4G	Benign	0.83	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.42		Gain of methylation at N840 (P = 0.0157);
MVP		0.61
MPC		0.19
ClinPred		0.11	T
GERP RS		-3.1
Varity_R		0.080
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs990269402; hg19: chr4-115749071;