rs114077338

chr15-23686265-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: NDN NM_002487.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.28

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 445448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDN	NM_002487.3	c.953T>C	p.Val318Ala	missense_variant	1/1	ENST00000649030.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDN	ENST00000649030.2	c.953T>C	p.Val318Ala	missense_variant	1/1		NM_002487.3	P1

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 527 AN: 152014 Hom.: 3 Cov.: 32

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

GnomAD3 exomes AF: 0.00113 AC: 195 AN: 173256 Hom.: 2 AF XY: 0.000794 AC XY: 73 AN XY: 91932

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 SAS 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.: 1 Cov.: 31 AF XY: 0.000285 AC XY: 189 AN XY: 663552

Gnomad4 AFR exome AF: 0.0138

Gnomad4 AMR exome AF: 0.000388

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: 0.00000188

Gnomad4 OTH exome AF: 0.000484

GnomAD4 genome AF: 0.00346 AC: 526 AN: 152134 Hom.: 3 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74376

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00250 Hom.: 1

Bravo AF: 0.00356

ESP6500AA AF: 0.00890 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000947 AC: 112

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 11, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.83	D
MetaRNN	Benign	0.0071	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.76	N;N
MutationTaster	Benign	0.94	N
PrimateAI	Uncertain	0.65	T
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	T
GERP RS		3.5
Varity_R		0.081
gMVP		0.26

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

Other links and lift over

dbSNP: rs114077338; hg19: chr15-23931412;