3-39143710-G-A

Variant names:

• chr3-39143710-G-A
• rs201834210
• NM_033027.4:c.1115C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033027.4(CSRNP1):​c.1115C>T​(p.Pro372Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,614,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: CSRNP1 NM_033027.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

Genes affected

CSRNP1 (HGNC:14300): (cysteine and serine rich nuclear protein 1) This gene encodes a protein that localizes to the nucleus and expression of this gene is induced in response to elevated levels of axin. The Wnt signalling pathway, which is negatively regulated by axin, is important in axis formation in early development and impaired regulation of this signalling pathway is often involved in tumors. A decreased level of expression of this gene in tumors compared to the level of expression in their corresponding normal tissues suggests that this gene product has a tumor suppressor function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03635633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSRNP1	NM_033027.4	c.1115C>T	p.Pro372Leu	missense_variant	Exon 5 of 5	ENST00000273153.10	NP_149016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRNP1	ENST00000273153.10	c.1115C>T	p.Pro372Leu	missense_variant	Exon 5 of 5	1	NM_033027.4	ENSP00000273153.5
CSRNP1	ENST00000514182.1	c.1115C>T	p.Pro372Leu	missense_variant	Exon 5 of 5	1		ENSP00000422532.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000439 AC: 11 AN: 250536 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135422

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000588 AC: 86 AN: 1461888 Hom.: 0 Cov.: 82 AF XY: 0.0000688 AC XY: 50 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

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: 0.0000701

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.0000537 AC XY: 4 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1115C>T (p.P372L) alteration is located in exon 5 (coding exon 4) of the CSRNP1 gene. This alteration results from a C to T substitution at nucleotide position 1115, causing the proline (P) at amino acid position 372 to be replaced by a leucine (L). 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	0.070
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.54
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.63	.;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.036	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.027
Sift	Benign	0.23	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.012	B;B
Vest4		0.051
MutPred		0.17		Loss of glycosylation at P375 (P = 0.0515);Loss of glycosylation at P375 (P = 0.0515);
MVP		0.10
MPC		0.25
ClinPred		0.024	T
GERP RS		2.7
Varity_R		0.025
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201834210; hg19: chr3-39185201;