Genetic Variant RNASE4:p.Thr16Ser (chr14-20699417-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002937.5(RNASE4):c.46A>T(p.Thr16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,608,562 control chromosomes in the GnomAD database, including 18,511 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.12 ( 1245 hom., cov: 32)

Exomes 𝑓: 0.15 ( 17266 hom. )

Consequence

RNASE4
NM_002937.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.01

Variant links:

Genes affected

RNASE4 (HGNC:10047): (ribonuclease A family member 4) The protein encoded by this gene belongs to the pancreatic ribonuclease family. It plays an important role in mRNA cleavage and has marked specificity towards the 3' side of uridine nucleotides. Alternative splicing results in four transcript variants encoding the same protein. This gene and the gene that encodes angiogenin share promoters and 5' exons. Each gene splices to a unique downstream exon that contains its complete coding region. [provided by RefSeq, Aug 2013]

RNASE4 links:

ENSG00000259171 (HGNC:):

ENSG00000259171 links:

EGILA (HGNC:54482): (EGFR interacting lncRNA)

EGILA links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018668771).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASE4	NM_002937.5 link	c.46A>T	p.Thr16Ser	missense_variant	Exon 2 of 2	ENST00000555835.3	NP_002928.1	P34096Q53XB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASE4	ENST00000555835.3 link	c.46A>T	p.Thr16Ser	missense_variant	Exon 2 of 2	1	NM_002937.5	ENSP00000452245.1		P34096
ENSG00000259171	ENST00000553909.1 link	c.*53A>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000477037.1		V9GYS4

Frequencies

GnomAD3 genomes

AF:

0.115

AC:

17507

AN:

151830

Hom.:

1246

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0280

Gnomad AMI

AF:

0.150

Gnomad AMR

AF:

0.117

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.212

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.172

Gnomad NFE

AF:

0.146

Gnomad OTH

AF:

0.115

GnomAD3 exomes

AF:

0.146

AC:

36625

AN:

250066

Hom.:

3007

AF XY:

0.153

AC XY:

20698

AN XY:

135168

show subpopulations

Gnomad AFR exome

AF:

0.0260

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.180

Gnomad EAS exome

AF:

0.196

Gnomad SAS exome

AF:

0.222

Gnomad FIN exome

AF:

0.139

Gnomad NFE exome

AF:

0.142

Gnomad OTH exome

AF:

0.140

GnomAD4 exome

AF:

0.149

AC:

217739

AN:

1456614

Hom.:

17266

Cov.:

AF XY:

0.152

AC XY:

110300

AN XY:

723650

show subpopulations

Gnomad4 AFR exome

AF:

0.0231

Gnomad4 AMR exome

AF:

0.117

Gnomad4 ASJ exome

AF:

0.175

Gnomad4 EAS exome

AF:

0.223

Gnomad4 SAS exome

AF:

0.219

Gnomad4 FIN exome

AF:

0.133

Gnomad4 NFE exome

AF:

0.147

Gnomad4 OTH exome

AF:

0.151

GnomAD4 genome

AF:

0.115

AC:

17506

AN:

151948

Hom.:

1245

Cov.:

AF XY:

0.118

AC XY:

8738

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.0279

Gnomad4 AMR

AF:

0.117

Gnomad4 ASJ

AF:

0.165

Gnomad4 EAS

AF:

0.211

Gnomad4 SAS

AF:

0.218

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.146

Gnomad4 OTH

AF:

0.117

Alfa

AF:

0.131

Hom.:

946

Bravo

AF:

0.108

TwinsUK

AF:

0.141

AC:

522

ALSPAC

AF:

0.143

AC:

552

ESP6500AA

AF:

0.0320

AC:

141

ESP6500EA

AF:

0.146

AC:

1256

ExAC

AF:

0.145

AC:

17561

Asia WGS

AF:

0.194

AC:

674

AN:

3478

EpiCase

AF:

0.151

EpiControl

AF:

0.148

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0033

T;T;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.50

.;.;T

MetaRNN

Benign

0.0019

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.90

N;N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.0030

D;D;D

Sift4G

Benign

0.38

T;T;T

Polyphen

0.97

D;D;D

Vest4

0.12

MutPred

0.23

Gain of catalytic residue at L12 (P = 0.0041);Gain of catalytic residue at L12 (P = 0.0041);Gain of catalytic residue at L12 (P = 0.0041);

MPC

0.30

ClinPred

0.029

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.38

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over