16-58503823-G-A

Variant names:

• chr16-58503823-G-A
• rs747496947
• NM_001242835.2:c.47G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001242835.2(NDRG4):​c.47G>A​(p.Gly16Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,613,786 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: NDRG4 NM_001242835.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.53

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDRG4	NM_001242835.2	c.47G>A	p.Gly16Asp	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.47G>A	p.Gly16Asp	missense_variant	Exon 2 of 15	1	NM_001242835.2	ENSP00000457659.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251202 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000773 AC: 113 AN: 1461714 Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54 AN XY: 727150

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74278

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000581 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.203G>A (p.G68D) alteration is located in exon 4 (coding exon 4) of the NDRG4 gene. This alteration results from a G to A substitution at nucleotide position 203, causing the glycine (G) at amino acid position 68 to be replaced by an aspartic acid (D). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;.;.;T;T;T;.;.;T;T;T;T;.;.;T;.;.;.;.;.;T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.035	D
MutationAssessor	Pathogenic	3.5	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M;.;.;.;M;.;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.4	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.55, 0.89, 1.0, 0.82, 1.0	.;.;P;.;.;.;.;P;.;.;.;.;P;.;.;D;.;.;.;P;.;D
Vest4		0.98, 0.97, 0.98, 0.94, 0.99
MutPred		0.79		.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of loop (P = 0.069);.;.;.;Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MVP		0.84
MPC		1.1
ClinPred		0.88	D
GERP RS		4.3
Varity_R		0.89
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs747496947; hg19: chr16-58537727;