Genetic Variant NDRG4:p.Asp10Glu (chr16-58503806-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001242835.2(NDRG4):c.30C>G(p.Asp10Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,698 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: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NDRG4
NM_001242835.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.937

Variant links:

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]

NDRG4 links:

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ACMG classification

Classification made for transcript

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=0.31558853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDRG4	NM_001242835.2 link	c.30C>G	p.Asp10Glu	missense_variant	Exon 2 of 15	ENST00000570248.6	NP_001229764.1	Q9ULP0-1A0A0S2Z5R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDRG4	ENST00000570248.6 link	c.30C>G	p.Asp10Glu	missense_variant	Exon 2 of 15	1	NM_001242835.2	ENSP00000457659.1		Q9ULP0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251126

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135792

show subpopulations

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000284

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.186C>G (p.D62E) alteration is located in exon 4 (coding exon 4) of the NDRG4 gene. This alteration results from a C to G substitution at nucleotide position 186, causing the aspartic acid (D) at amino acid position 62 to be replaced by a glutamic acid (E). 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

0.48

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.013

.;.;.;T;T;T;.;.;T;T;T;T;.;.;T;.;.;.;.;.;T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.89

D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.037

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

MutationAssessor

Benign

1.8

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;.;.;.;L;.;L

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.7

D;D;N;D;D;D;D;N;D;D;D;D;N;D;D;N;D;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.11

T;D;D;T;D;D;D;D;D;.;D;D;D;T;D;D;D;D;D;D;D;D

Sift4G

Benign

0.13

T;T;T;D;D;T;T;T;D;D;T;T;T;T;T;D;D;D;D;D;D;D

Polyphen

0.37, 0.66, 0.99, 0.47, 1.0

.;.;B;.;.;.;.;P;.;.;.;.;B;.;.;D;.;.;.;P;.;D

Vest4

0.86, 0.87, 0.86, 0.87, 0.83, 0.85, 0.83, 0.86, 0.89

MutPred

0.43

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of disorder (P = 0.1136);.;.;.;Gain of disorder (P = 0.1136);Gain of disorder (P = 0.1136);Gain of disorder (P = 0.1136);

MVP

0.34

MPC

0.68

ClinPred

0.78

GERP RS

2.3

Varity_R

0.15

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over