chr4-105938382-C-T

Variant names:

• chr4-105938382-C-T
• rs116477289
• NM_001033047.3:c.467C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001033047.3(NPNT):​c.467C>T​(p.Pro156Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000415 in 1,613,722 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: NPNT NM_001033047.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.48
• Publications: 6 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014282137).
• BP6: Variant 4-105938382-C-T is Benign according to our data. Variant chr4-105938382-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2655006.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.467C>T	p.Pro156Leu	missense	Exon 5 of 12	NP_001028219.1	Q6UXI9-1
	NPNT	NM_001184691.2		c.557C>T	p.Pro186Leu	missense	Exon 6 of 13	NP_001171620.1	Q6UXI9-3
	NPNT	NM_001184690.2		c.518C>T	p.Pro173Leu	missense	Exon 6 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.467C>T	p.Pro156Leu	missense	Exon 5 of 12	ENSP00000369323.2	Q6UXI9-1
	NPNT	ENST00000305572.12	TSL:1	c.467C>T	p.Pro156Leu	missense	Exon 5 of 11	ENSP00000302557.8	Q6UXI9-2
	NPNT	ENST00000876321.1		c.623C>T	p.Pro208Leu	missense	Exon 7 of 14	ENSP00000546380.1

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 321 AN: 152184 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00739

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000523 AC: 131 AN: 250308 AF XY: 0.000384

Gnomad AFR exome AF: 0.00721

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000239 AC: 350 AN: 1461420 Hom.: 2 Cov.: 30 AF XY: 0.000212 AC XY: 154 AN XY: 727056

African (AFR) AF: 0.00706 AC: 236 AN: 33450

American (AMR) AF: 0.000134 AC: 6 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53400

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1111734

Other (OTH) AF: 0.000563 AC: 34 AN: 60378

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152302 Hom.: 1 Cov.: 33 AF XY: 0.00196 AC XY: 146 AN XY: 74466

African (AFR) AF: 0.00734 AC: 305 AN: 41556

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000888 Hom.: 1

Bravo AF: 0.00228

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000675 AC: 82

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.73
Sift	Benign	0.032	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.79
MVP		0.74
MPC		0.12
ClinPred		0.091	T
GERP RS		5.2
Varity_R		0.33
gMVP		0.72
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs116477289; hg19: chr4-106859539;