16-58503843-C-T

Variant names:

• chr16-58503843-C-T
• rs145564006
• NM_001242835.2:c.67C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001363869.2(NDRG4):​c.-99C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: NDRG4 NM_001363869.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

Genes affected

NDRG4 (HGNC:14466): (NDRG family member 4) This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein that is required for cell cycle progression and survival in primary astrocytes and may be involved in the regulation of mitogenic signalling in vascular smooth muscles cells. Alternative splicing results in multiple transcripts encoding different isoforms.[provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31855395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDRG4	NM_001242835.2	c.67C>T	p.Arg23Trp	missense_variant	Exon 2 of 15	ENST00000570248.6	NP_001229764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDRG4	ENST00000570248.6	c.67C>T	p.Arg23Trp	missense_variant	Exon 2 of 15	1	NM_001242835.2	ENSP00000457659.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000132

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251236 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135826

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461742 Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74446

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.223C>T (p.R75W) alteration is located in exon 4 (coding exon 4) of the NDRG4 gene. This alteration results from a C to T substitution at nucleotide position 223, causing the arginine (R) at amino acid position 75 to be replaced by a tryptophan (W). 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	Uncertain	0.36
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	.;.;.;T;T;T;.;.;T;T;T;T;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;.;.;.;L;.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.5	D;D;N;D;D;D;D;N;D;D;D;D;N;D;D;N;D;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.095	T;D;T;T;T;D;D;T;T;.;T;D;T;T;D;T;D;T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.051, 0.026, 0.096, 0.079	.;.;B;.;.;.;.;B;.;.;.;.;B;.;.;B;.;.;.;B;.;B
Vest4		0.80, 0.82, 0.82, 0.74, 0.82, 0.72, 0.83
MVP		0.41
MPC		0.31
ClinPred		0.14	T
GERP RS		3.3
Varity_R		0.18
gMVP		0.84

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: rs145564006; hg19: chr16-58537747; COSMIC: COSV50749372; COSMIC: COSV50749372;