4-105937045-A-C

Variant names:

• chr4-105937045-A-C
• NM_001033047.3:c.302A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001033047.3(NPNT):​c.302A>C​(p.Lys101Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPNT NM_001033047.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033047.3. 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
	NPNT	NM_001033047.3	MANE Select	c.302A>C	p.Lys101Thr	missense	Exon 4 of 12	NP_001028219.1	Q6UXI9-1
	NPNT	NM_001184691.2		c.392A>C	p.Lys131Thr	missense	Exon 5 of 13	NP_001171620.1	Q6UXI9-3
	NPNT	NM_001184690.2		c.353A>C	p.Lys118Thr	missense	Exon 5 of 13	NP_001171619.1	Q6UXI9-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPNT	ENST00000379987.7	TSL:1 MANE Select	c.302A>C	p.Lys101Thr	missense	Exon 4 of 12	ENSP00000369323.2	Q6UXI9-1
	NPNT	ENST00000305572.12	TSL:1	c.302A>C	p.Lys101Thr	missense	Exon 4 of 11	ENSP00000302557.8	Q6UXI9-2
	NPNT	ENST00000876321.1		c.443A>C	p.Lys148Thr	missense	Exon 6 of 14	ENSP00000546380.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.13	N
PhyloP100		9.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.72
MutPred		0.52		Loss of methylation at K101 (P = 2e-04)
MVP		0.66
MPC		0.37
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.54
gMVP		0.68
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr4-106858202;