Genetic Variant NDRG4:c.133-131delA (chr16-58494832-TA-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.133-117delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0354 in 536,648 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 0.00049 ( 0 hom., cov: 0)

Exomes 𝑓: 0.047 ( 0 hom. )

Consequence

NDRG4
NM_001378332.1 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.525

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:

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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 (0.0764) population. However there is too low homozygotes in high coverage region: (expected more than 167, 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.133-117delA	intron	N/A	NP_001365261.1
NDRG4	NM_001378333.1	c.133-117delA	intron	N/A	NP_001365262.1
NDRG4	NM_001378334.1	c.133-117delA	intron	N/A	NP_001365263.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.000489

AC:

AN:

135012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000358

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000742

Gnomad ASJ

AF:

0.000301

Gnomad EAS

AF:

0.000214

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00271

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000487

Gnomad OTH

AF:

0.000556

GnomAD4 exome

AF:

0.0471

AC:

18920

AN:

401658

Hom.:

AF XY:

0.0485

AC XY:

10173

AN XY:

209942

show subpopulations

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

African (AFR)

AF:

0.0255

AC:

274

AN:

10736

American (AMR)

AF:

0.0252

AC:

406

AN:

16122

Ashkenazi Jewish (ASJ)

AF:

0.0517

AC:

580

AN:

11210

East Asian (EAS)

AF:

0.0416

AC:

1106

AN:

26578

South Asian (SAS)

AF:

0.0789

AC:

2721

AN:

34478

European-Finnish (FIN)

AF:

0.0422

AC:

1030

AN:

24428

Middle Eastern (MID)

AF:

0.0470

AC:

AN:

2022

European-Non Finnish (NFE)

AF:

0.0460

AC:

11713

AN:

254376

Other (OTH)

AF:

0.0458

AC:

995

AN:

21708

⚠️ 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: 0.309

Heterozygous variant carriers

1406

2812

4218

5624

7030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

194

388

582

776

970

<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:

0.000489

AC:

AN:

134990

Hom.:

Cov.:

AF XY:

0.000513

AC XY:

AN XY:

64358

show subpopulations

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

African (AFR)

AF:

0.000358

AC:

AN:

36332

American (AMR)

AF:

0.0000742

AC:

AN:

13478

Ashkenazi Jewish (ASJ)

AF:

0.000301

AC:

AN:

3318

East Asian (EAS)

AF:

0.000215

AC:

AN:

4656

South Asian (SAS)

AF:

0.00

AC:

AN:

4020

European-Finnish (FIN)

AF:

0.00271

AC:

AN:

6634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

258

European-Non Finnish (NFE)

AF:

0.000487

AC:

AN:

63614

Other (OTH)

AF:

0.000553

AC:

AN:

1808

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.352

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

-0.53

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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16-58494832-TAAAAAAAAAAA-TAAAAAAAAAA

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