15-23686832-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002487.3(NDN):c.386T>C(p.Ile129Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NDN NM_002487.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29398233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDN	NM_002487.3	c.386T>C	p.Ile129Thr	missense_variant	1/1	ENST00000649030.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDN	ENST00000649030.2	c.386T>C	p.Ile129Thr	missense_variant	1/1		NM_002487.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.386T>C (p.I129T) alteration is located in exon 1 (coding exon 1) of the NDN gene. This alteration results from a T to C substitution at nucleotide position 386, causing the isoleucine (I) at amino acid position 129 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.46	N
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.93	N
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.3	D;.
REVEL	Benign	0.12
Sift	Uncertain	0.016	D;.
Sift4G	Uncertain	0.0050	D;.
Polyphen		0.15	B;B
Vest4		0.37
MutPred		0.64		Gain of phosphorylation at I129 (P = 0.0322);Gain of phosphorylation at I129 (P = 0.0322);
MVP		0.39
MPC		1.4
ClinPred		0.83	D
GERP RS		2.8
Varity_R		0.30
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-23931979;