NM_015392.4:c.407G>C

Variant names:

• chr9-137040963-C-G
• rs778983633
• NM_015392.4:c.407G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015392.4(NPDC1):​c.407G>C​(p.Arg136Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,392,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: NPDC1 NM_015392.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.15
• Publications: 0 publications found

Genes affected

NPDC1 (HGNC:7899): (neural proliferation, differentiation and control 1) Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05888471).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015392.4. 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
	NPDC1	NM_015392.4	MANE Select	c.407G>C	p.Arg136Pro	missense	Exon 4 of 9	NP_056207.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPDC1	ENST00000371601.5	TSL:1 MANE Select	c.407G>C	p.Arg136Pro	missense	Exon 4 of 9	ENSP00000360660.4	Q9NQX5
	NPDC1	ENST00000371600.7	TSL:1	c.641G>C	p.Arg214Pro	missense	Exon 3 of 8	ENSP00000360659.3	Q5SPY9
	NPDC1	ENST00000952624.1		c.407G>C	p.Arg136Pro	missense	Exon 4 of 9	ENSP00000622683.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1392042 Hom.: 0 Cov.: 33 AF XY: 0.00000437 AC XY: 3 AN XY: 686154

African (AFR) AF: 0.00 AC: 0 AN: 30880

American (AMR) AF: 0.00 AC: 0 AN: 32546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21542

East Asian (EAS) AF: 0.00 AC: 0 AN: 39094

South Asian (SAS) AF: 0.00 AC: 0 AN: 75486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1080368

Other (OTH) AF: 0.0000175 AC: 1 AN: 57278

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.64
DANN	Benign	0.67
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		-3.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.024
Sift	Benign	0.057	T
Sift4G	Benign	0.28	T
Polyphen		0.0020	B
Vest4		0.21
MutPred		0.53		Loss of methylation at R214 (P = 0.0143)
MVP		0.043
MPC		0.10
ClinPred		0.070	T
GERP RS		-6.8
Varity_R		0.15
gMVP		0.41
Mutation Taster		=91/9	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: rs778983633; hg19: chr9-139935415;