Genetic Variant NDRG4:c.37+8C>A (chr16-58464475-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001378332.1(NDRG4):c.37+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000932 in 1,316,936 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0049 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 8 hom. )

Consequence

NDRG4
NM_001378332.1 splice_region, intron

Scores

Splicing: ADA: 0.0001219

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.170

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 16-58464475-C-A is Benign according to our data. Variant chr16-58464475-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1697107.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00489 (744/152278) while in subpopulation AFR AF= 0.0172 (715/41580). AF 95% confidence interval is 0.0162. There are 7 homozygotes in gnomad4. There are 355 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
NDRG4	NM_001378332.1 link	c.37+8C>A	splice_region_variant, intron_variant	Intron 1 of 17	NP_001365261.1
NDRG4	NM_001378333.1 link	c.37+8C>A	splice_region_variant, intron_variant	Intron 1 of 16	NP_001365262.1
NDRG4	NM_001378334.1 link	c.37+8C>A	splice_region_variant, intron_variant	Intron 1 of 16	NP_001365263.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
NDRG4	ENST00000394282.8 link	c.37+8C>A	splice_region_variant, intron_variant	Intron 1 of 15	1	ENSP00000377823.4	Q9ULP0-6
NDRG4	ENST00000258187.9 link	c.-24+678C>A	intron_variant	Intron 1 of 15	1	ENSP00000258187.5	Q9ULP0-3
NDRG4	ENST00000564126.5 link	c.-24+678C>A	intron_variant	Intron 1 of 7	3	ENSP00000454216.1	H3BM40

Frequencies

GnomAD3 genomes

AF:

0.00488

AC:

743

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0172

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.0000441

Gnomad OTH

AF:

0.00191

GnomAD4 exome

AF:

0.000416

AC:

484

AN:

1164658

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

193

AN XY:

559568

show subpopulations

Gnomad4 AFR exome

AF:

0.0179

Gnomad4 AMR exome

AF:

0.00100

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:

0.00000726

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.00489

AC:

744

AN:

152278

Hom.:

Cov.:

AF XY:

0.00477

AC XY:

355

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0172

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.00506

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 15, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

9.7

DANN

Benign

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.0040

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