14-20802029-C-A

Variant summary

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

The NM_002933.5(RNASE1):​c.40G>T​(p.Val14Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,605,556 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

RNASE1
NM_002933.5 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.715
Variant links:
Genes affected
RNASE1 (HGNC:10044): (ribonuclease A family member 1, pancreatic) This gene encodes a member of the pancreatic-type of secretory ribonucleases, a subset of the ribonuclease A superfamily. The encoded endonuclease cleaves internal phosphodiester RNA bonds on the 3'-side of pyrimidine bases. It prefers poly(C) as a substrate and hydrolyzes 2',3'-cyclic nucleotides, with a pH optimum near 8.0. The encoded protein is monomeric and more commonly acts to degrade ds-RNA over ss-RNA. Alternative splicing occurs at this locus and four transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RNASE1NM_002933.5 linkuse as main transcriptc.40G>T p.Val14Phe missense_variant 2/2 ENST00000397967.5
LOC105370397XR_007064063.1 linkuse as main transcriptn.277-7810C>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RNASE1ENST00000397967.5 linkuse as main transcriptc.40G>T p.Val14Phe missense_variant 2/21 NM_002933.5 P1

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152062
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
GnomAD3 exomes
AF:
0.0000902
AC:
22
AN:
243926
Hom.:
0
AF XY:
0.0000831
AC XY:
11
AN XY:
132372
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000581
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000245
Gnomad NFE exome
AF:
0.000133
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000323
AC:
47
AN:
1453494
Hom.:
0
Cov.:
31
AF XY:
0.0000332
AC XY:
24
AN XY:
723312
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000110
Gnomad4 NFE exome
AF:
0.0000342
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
152062
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74276
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
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:
0.00
Alfa
AF:
0.000182
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 04, 2024The c.40G>T (p.V14F) alteration is located in exon 3 (coding exon 1) of the RNASE1 gene. This alteration results from a G to T substitution at nucleotide position 40, causing the valine (V) at amino acid position 14 to be replaced by a phenylalanine (F). 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
0.097
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
13
DANN
Uncertain
0.99
DEOGEN2
Benign
0.17
T;T;T;T
Eigen
Benign
-0.080
Eigen_PC
Benign
-0.33
FATHMM_MKL
Benign
0.061
N
LIST_S2
Uncertain
0.86
.;.;.;D
M_CAP
Uncertain
0.14
D
MetaRNN
Uncertain
0.46
T;T;T;T
MetaSVM
Uncertain
-0.27
T
MutationAssessor
Uncertain
2.7
M;M;M;M
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.9
N;N;N;N
REVEL
Uncertain
0.47
Sift
Uncertain
0.0050
D;D;D;D
Sift4G
Benign
0.17
T;T;T;T
Polyphen
1.0
D;D;D;D
Vest4
0.38
MutPred
0.54
Gain of catalytic residue at V19 (P = 0.0648);Gain of catalytic residue at V19 (P = 0.0648);Gain of catalytic residue at V19 (P = 0.0648);Gain of catalytic residue at V19 (P = 0.0648);
MVP
0.93
MPC
0.60
ClinPred
0.11
T
GERP RS
3.1
Varity_R
0.14
gMVP
0.82

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs773558626; hg19: chr14-21270188; API