Genetic Variant RNASE7:p.Val26Leu (chr14-21043068-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032572.4(RNASE7):c.76G>C(p.Val26Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

RNASE7
NM_032572.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.75

Variant links:

Genes affected

RNASE7 (HGNC:19278): (ribonuclease A family member 7) The protein encoded by this gene belongs to the pancreatic ribonuclease family, a subset of the ribonuclease A superfamily. The protein has broad-spectrum antimicrobial activity against bacteria and fungi. [provided by RefSeq, Oct 2014]

RNASE7 links:

NDRG2 (HGNC:14460): (NDRG family member 2) This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein that may play a role in neurite outgrowth. This gene may be involved in glioblastoma carcinogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

NDRG2 links:

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ACMG classification

Classification made for transcript

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=0.05432272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASE7	NM_032572.4 link	c.76G>C	p.Val26Leu	missense_variant	Exon 2 of 2	ENST00000298690.5	NP_115961.3	Q9H1E1
NDRG2	NM_001282211.2 link	c.25-19747C>G		intron_variant	Intron 1 of 14		NP_001269140.1	Q9UN36-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RNASE7	ENST00000298690.5 link	c.76G>C	p.Val26Leu	missense_variant	Exon 2 of 2	1	NM_032572.4	ENSP00000298690.3	Q9H1E1
NDRG2	ENST00000403829.7 link	c.25-19747C>G		intron_variant	Intron 1 of 14	2		ENSP00000385889.3	Q9UN36-6
NDRG2	ENST00000555026.5 link	c.-7+3798C>G		intron_variant	Intron 2 of 12	5		ENSP00000451274.1	G3V5H8
RNASE7	ENST00000481538.1 link	n.76G>C		non_coding_transcript_exon_variant	Exon 2 of 3	2		ENSP00000431382.1	Q9H1E1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000917

AC:

AN:

250954

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.76G>C (p.V26L) alteration is located in exon 2 (coding exon 1) of the RNASE7 gene. This alteration results from a G to C substitution at nucleotide position 76, causing the valine (V) at amino acid position 26 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

0.19

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.0024

Eigen

Benign

0.088

Eigen_PC

Benign

0.060

FATHMM_MKL

Uncertain

0.81

M_CAP

Benign

0.019

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.22

REVEL

Benign

0.27

Sift

Benign

0.93

Sift4G

Benign

0.87

Polyphen

1.0

Vest4

0.11

MVP

0.88

MPC

0.21

ClinPred

1.0

GERP RS

5.1

Varity_R

0.068

gMVP

0.43

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over