Genetic Variant NM_002487.3:c.953T>C (chr15-23686265-A-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002487.3(NDN):c.953T>C(p.Val318Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,509,528 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

NDN
NM_002487.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.28

Publications

4 publications found

Variant links:

Genes affected

NDN (HGNC:7675): (necdin, MAGE family member) This intronless gene is located in the Prader-Willi syndrome deletion region. It is an imprinted gene and is expressed exclusively from the paternal allele. Studies in mouse suggest that the protein encoded by this gene may suppress growth in postmitotic neurons. [provided by RefSeq, Jul 2008]

NDN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007107556).

BP6

Variant 15-23686265-A-G is Benign according to our data. Variant chr15-23686265-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDN	NM_002487.3 link	c.953T>C	p.Val318Ala	missense_variant	Exon 1 of 1	ENST00000649030.2	NP_002478.1	Q99608X5D982

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDN	ENST00000649030.2 link	c.953T>C	p.Val318Ala	missense_variant	Exon 1 of 1		NM_002487.3	ENSP00000497916.1		Q99608

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

527

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00113

AC:

195

AN:

173256

AF XY:

0.000794

show subpopulations

Gnomad AFR exome

AF:

0.0128

Gnomad AMR exome

AF:

0.000343

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000753

GnomAD4 exome

AF:

0.000336

AC:

456

AN:

1357394

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

189

AN XY:

663552

show subpopulations

African (AFR)

AF:

0.0138

AC:

416

AN:

30048

American (AMR)

AF:

0.000388

AC:

AN:

28366

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19832

East Asian (EAS)

AF:

0.00

AC:

AN:

38640

South Asian (SAS)

AF:

0.00

AC:

AN:

69494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48972

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3670

European-Non Finnish (NFE)

AF:

0.00000188

AC:

AN:

1062604

Other (OTH)

AF:

0.000484

AC:

AN:

55768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00346

AC:

526

AN:

152134

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

268

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0123

AC:

509

AN:

41510

American (AMR)

AF:

0.000720

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67990

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00250

Hom.:

Bravo

AF:

0.00356

ESP6500AA

AF:

0.00890

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000947

AC:

112

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 11, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.64

.;T

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.76

N;N

PhyloP100

2.3

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.68

N;.

REVEL

Benign

0.047

Sift

Uncertain

0.0020

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.38

B;B

Vest4

0.20

MVP

0.20

MPC

0.92

ClinPred

0.025

GERP RS

3.5

Varity_R

0.081

gMVP

0.26

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over