rs114077338

Variant names:

• chr15-23686265-A-G
• rs114077338
• NM_002487.3:c.953T>C

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.28
• Publications: 4 publications found

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002487.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDN	NM_002487.3	MANE Select	c.953T>C	p.Val318Ala	missense	Exon 1 of 1	NP_002478.1	X5D982

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDN	ENST00000649030.2	MANE Select	c.953T>C	p.Val318Ala	missense	Exon 1 of 1	ENSP00000497916.1	Q99608

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

GnomAD2 exomes AF: 0.00113 AC: 195 AN: 173256 AF XY: 0.000794

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

African (AFR) AF: 0.0138 AC: 416 AN: 30048

American (AMR) AF: 0.000388 AC: 11 AN: 28366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19832

East Asian (EAS) AF: 0.00 AC: 0 AN: 38640

South Asian (SAS) AF: 0.00 AC: 0 AN: 69494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3670

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1062604

Other (OTH) AF: 0.000484 AC: 27 AN: 55768

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

African (AFR) AF: 0.0123 AC: 509 AN: 41510

American (AMR) AF: 0.000720 AC: 11 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67990

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.76	N
PhyloP100		2.3
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
Vest4		0.20
MVP		0.20
MPC		0.92
ClinPred		0.025	T
GERP RS		3.5
Varity_R		0.081
gMVP		0.26
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs114077338; hg19: chr15-23931412;