4-105895711-A-G

Position:

• chr4-105895711-A-G

Variant summary

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

The NM_001033047.3(NPNT):​c.59A>G​(p.Glu20Gly) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E20A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPNT NM_001033047.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

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]

INTS12 (HGNC:25067): (integrator complex subunit 12) INTS12 is a subunit of the Integrator complex, which associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A; MIM 180660) and mediates 3-prime end processing of small nuclear RNAs U1 (RNU1; MIM 180680) and U2 (RNU2; MIM 180690) (Baillat et al., 2005 [PubMed 16239144]).[supplied by OMIM, Mar 2008]

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=0.2056379).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPNT	NM_001033047.3	c.59A>G	p.Glu20Gly	missense_variant	1/12	ENST00000379987.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPNT	ENST00000379987.7	c.59A>G	p.Glu20Gly	missense_variant	1/12	1	NM_001033047.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1401096 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 691286

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Dec 27, 2022

The c.59A>G (p.E20G) alteration is located in exon 1 (coding exon 1) of the NPNT gene. This alteration results from a A to G substitution at nucleotide position 59, causing the glutamic acid (E) at amino acid position 20 to be replaced by a glycine (G). 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	0.12
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T;.;.;.;.;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;L;L;L;L;.
MutationTaster	Benign	0.99	N;N;N;N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.13	T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T
Polyphen		0.55	P;.;.;.;P;.;.
Vest4		0.24
MutPred		0.51		Gain of catalytic residue at A19 (P = 0.024);Gain of catalytic residue at A19 (P = 0.024);Gain of catalytic residue at A19 (P = 0.024);Gain of catalytic residue at A19 (P = 0.024);Gain of catalytic residue at A19 (P = 0.024);Gain of catalytic residue at A19 (P = 0.024);Gain of catalytic residue at A19 (P = 0.024);
MVP		0.60
MPC		0.095
ClinPred		0.65	D
GERP RS		3.4
Varity_R		0.10
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr4-106816868;