rs4340795

Positions:

• chr4-105940573-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001033047.3(NPNT):​c.700A>G​(p.Ile234Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.908 in 1,612,610 control chromosomes in the GnomAD database, including 667,032 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.87 (57952 hom., cov: 32)
  • Exomes 𝑓: 0.91 (609080 hom.)
• Consequence: NPNT NM_001033047.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.603

Genes affected

NPNT (HGNC:27405): (nephronectin) Predicted to enable integrin binding activity. Predicted to be involved in several processes, including cell-cell adhesion mediated by integrin; positive regulation of ERK1 and ERK2 cascade; and positive regulation of osteoblast differentiation. Predicted to act upstream of or within positive regulation of transforming growth factor beta receptor signaling pathway. Located in extracellular exosome. Part of collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3893782E-6).
• BP6: Variant 4-105940573-A-G is Benign according to our data. Variant chr4-105940573-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPNT	NM_001033047.3	c.700A>G	p.Ile234Val	missense_variant	7/12	ENST00000379987.7	NP_001028219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPNT	ENST00000379987.7	c.700A>G	p.Ile234Val	missense_variant	7/12	1	NM_001033047.3	ENSP00000369323.2

Frequencies

GnomAD3 genomes AF: 0.869 AC: 132041 AN: 152022 Hom.: 57936 Cov.: 32

Gnomad AFR AF: 0.727

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.910

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.955

Gnomad FIN AF: 0.945

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.913

Gnomad OTH AF: 0.880

GnomAD3 exomes AF: 0.920 AC: 230863 AN: 251052 Hom.: 106663 AF XY: 0.923 AC XY: 125194 AN XY: 135672

Gnomad AFR exome AF: 0.712

Gnomad AMR exome AF: 0.950

Gnomad ASJ exome AF: 0.931

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.947

Gnomad FIN exome AF: 0.937

Gnomad NFE exome AF: 0.915

Gnomad OTH exome AF: 0.929

GnomAD4 exome AF: 0.912 AC: 1332611 AN: 1460470 Hom.: 609080 Cov.: 35 AF XY: 0.914 AC XY: 664076 AN XY: 726582

Gnomad4 AFR exome AF: 0.713

Gnomad4 AMR exome AF: 0.947

Gnomad4 ASJ exome AF: 0.930

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.946

Gnomad4 FIN exome AF: 0.935

Gnomad4 NFE exome AF: 0.910

Gnomad4 OTH exome AF: 0.911

GnomAD4 genome AF: 0.868 AC: 132102 AN: 152140 Hom.: 57952 Cov.: 32 AF XY: 0.873 AC XY: 64963 AN XY: 74380

Gnomad4 AFR AF: 0.726

Gnomad4 AMR AF: 0.911

Gnomad4 ASJ AF: 0.929

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.954

Gnomad4 FIN AF: 0.945

Gnomad4 NFE AF: 0.913

Gnomad4 OTH AF: 0.881

Alfa AF: 0.908 Hom.: 162047

Bravo AF: 0.861

TwinsUK AF: 0.901 AC: 3340

ALSPAC AF: 0.906 AC: 3491

ESP6500AA AF: 0.732 AC: 3227

ESP6500EA AF: 0.910 AC: 7822

ExAC AF: 0.916 AC: 111196

Asia WGS AF: 0.959 AC: 3334 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.47
DANN	Benign	0.38
DEOGEN2	Benign	0.12	T;.;.;.;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.58	T;T;T;T;T;T;T
MetaRNN	Benign	0.0000014	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.045	N;.;.;N;N;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.68	N;N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.23	T;T;T;T;T;T;T
Sift4G	Benign	0.076	T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;B;.;B
Vest4		0.043
MPC		0.047
ClinPred		0.026	T
GERP RS		-9.7
Varity_R		0.045
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4340795; hg19: chr4-106861730;