rs4340795

Variant names:

• chr4-105940573-A-G
• rs4340795
• NM_001033047.3:c.700A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. 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.

• 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
• Publications: 30 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3893782E-6).
• 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 rank	MANE	Protein	UniProt
NPNT	NM_001033047.3	c.700A>G	p.Ile234Val	missense_variant	Exon 7 of 12	ENST00000379987.7	NP_001028219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPNT	ENST00000379987.7	c.700A>G	p.Ile234Val	missense_variant	Exon 7 of 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

GnomAD2 exomes AF: 0.920 AC: 230863 AN: 251052 AF XY: 0.923

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 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

African (AFR) AF: 0.713 AC: 23842 AN: 33432

American (AMR) AF: 0.947 AC: 42312 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.930 AC: 24290 AN: 26114

East Asian (EAS) AF: 1.00 AC: 39660 AN: 39666

South Asian (SAS) AF: 0.946 AC: 81581 AN: 86230

European-Finnish (FIN) AF: 0.935 AC: 49960 AN: 53406

Middle Eastern (MID) AF: 0.927 AC: 5345 AN: 5764

European-Non Finnish (NFE) AF: 0.910 AC: 1010645 AN: 1110844

Other (OTH) AF: 0.911 AC: 54976 AN: 60350

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

African (AFR) AF: 0.726 AC: 30105 AN: 41462

American (AMR) AF: 0.911 AC: 13914 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 3227 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5178 AN: 5178

South Asian (SAS) AF: 0.954 AC: 4602 AN: 4822

European-Finnish (FIN) AF: 0.945 AC: 10021 AN: 10608

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.913 AC: 62090 AN: 68008

Other (OTH) AF: 0.881 AC: 1858 AN: 2108

Alfa AF: 0.900 Hom.: 242381

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;.;.
PhyloP100		0.60
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4340795; hg19: chr4-106861730; COSMIC: COSV107369371; COSMIC: COSV107369371;