chr1-51789621-C-G

Position:

• chr1-51789621-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001101662.2(NRDC):​c.3205G>C​(p.Val1069Leu) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRDC NM_001101662.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

Genes affected

NRDC (HGNC:7995): (nardilysin convertase) This gene encodes a zinc-dependent endopeptidase that cleaves peptide substrates at the N-terminus of arginine residues in dibasic moieties and is a member of the peptidase M16 family. This protein interacts with heparin-binding EGF-like growth factor and plays a role in cell migration and proliferation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

OSBPL9 (HGNC:16386): (oxysterol binding protein like 9) This gene encodes a member of the oxysterol-binding protein (OSBP) family, a group of intracellular lipid receptors. Most members contain an N-terminal pleckstrin homology domain and a highly conserved C-terminal OSBP-like sterol-binding domain, although some members contain only the sterol-binding domain. This family member functions as a cholesterol transfer protein that regulates Golgi structure and function. Multiple transcript variants, most of which encode distinct isoforms, have been identified. Related pseudogenes have been identified on chromosomes 3, 11 and 12. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12771073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRDC	NM_001101662.2	c.3205G>C	p.Val1069Leu	missense_variant	30/31	ENST00000352171.12	NP_001095132.1
NRDC	NM_002525.3	c.3409G>C	p.Val1137Leu	missense_variant	32/33		NP_002516.2
NRDC	NM_001242361.2	c.3013G>C	p.Val1005Leu	missense_variant	32/33		NP_001229290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRDC	ENST00000352171.12	c.3205G>C	p.Val1069Leu	missense_variant	30/31	1	NM_001101662.2	ENSP00000262679	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Sep 17, 2021

The c.3409G>C (p.V1137L) alteration is located in exon 32 (coding exon 32) of the NRDC gene. This alteration results from a G to C substitution at nucleotide position 3409, causing the valine (V) at amino acid position 1137 to be replaced by a leucine (L). 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	Benign	0.17
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0077	.;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.46	N;N;N
REVEL	Benign	0.035
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.68	T;T;T
Vest4		0.23
MutPred		0.45		.;Gain of catalytic residue at V1137 (P = 0.0221);.;
MVP		0.11
MPC		0.53
ClinPred		0.23	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.092
gMVP		0.49

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: rs1678479864; hg19: chr1-52255293;