Genetic Variant NDRG4:c.133-131_133-130delAA (chr16-58494832-TAA-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378332.1(NDRG4):c.133-118_133-117delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 539,922 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0081 ( 0 hom. )

Consequence

NDRG4
NM_001378332.1 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.990

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

achromatopsia
Inheritance: AR Classification: LIMITED Submitted by: G2P

NDRG4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Variant has high frequency in the SAS (0.0158) population. However there is too low homozygotes in high coverage region: (expected more than 4, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378332.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
NDRG4	NM_001378332.1	c.133-118_133-117delAA	intron	N/A	NP_001365261.1
NDRG4	NM_001378333.1	c.133-118_133-117delAA	intron	N/A	NP_001365262.1
NDRG4	NM_001378334.1	c.133-118_133-117delAA	intron	N/A	NP_001365263.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NDRG4	ENST00000394282.8	TSL:1	c.133-131_133-130delAA	intron	N/A	ENSP00000377823.4	Q9ULP0-6
NDRG4	ENST00000258187.9	TSL:1	c.73-131_73-130delAA	intron	N/A	ENSP00000258187.5	Q9ULP0-3
NDRG4	ENST00000394279.6	TSL:5	c.73-131_73-130delAA	intron	N/A	ENSP00000377820.2	Q9ULP0-3

Frequencies

GnomAD3 genomes

AF:

0.0000444

AC:

AN:

135008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000551

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000301

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000302

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000157

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00809

AC:

3277

AN:

404914

Hom.:

AF XY:

0.00835

AC XY:

1768

AN XY:

211616

show subpopulations

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

African (AFR)

AF:

0.00359

AC:

AN:

10868

American (AMR)

AF:

0.00414

AC:

AN:

16440

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

11294

East Asian (EAS)

AF:

0.00702

AC:

189

AN:

26936

South Asian (SAS)

AF:

0.0169

AC:

588

AN:

34694

European-Finnish (FIN)

AF:

0.00788

AC:

194

AN:

24612

Middle Eastern (MID)

AF:

0.00293

AC:

AN:

2046

European-Non Finnish (NFE)

AF:

0.00761

AC:

1948

AN:

256142

Other (OTH)

AF:

0.00704

AC:

154

AN:

21882

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.264

Heterozygous variant carriers

338

675

1013

1350

1688

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000444

AC:

AN:

135008

Hom.:

Cov.:

AF XY:

0.0000622

AC XY:

AN XY:

64360

show subpopulations

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

African (AFR)

AF:

0.0000551

AC:

AN:

36284

American (AMR)

AF:

0.00

AC:

AN:

13468

Ashkenazi Jewish (ASJ)

AF:

0.000301

AC:

AN:

3318

East Asian (EAS)

AF:

0.00

AC:

AN:

4676

South Asian (SAS)

AF:

0.00

AC:

AN:

4048

European-Finnish (FIN)

AF:

0.000302

AC:

AN:

6624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0000157

AC:

AN:

63634

Other (OTH)

AF:

0.00

AC:

AN:

1800

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000378116), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.99

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over