14-20891949-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002935.3(RNASE3):c.263G>A(p.Arg88His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,612 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RNASE3 NM_002935.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.62

Genes affected

RNASE3 (HGNC:10046): (ribonuclease A family member 3) The protein encoded by this gene belongs to the pancreatic ribonuclease family, a subset of the ribonuclease A superfamily. The protein exhibits antimicrobial activity against pathogenic bacteria [provided by RefSeq, Oct 2014]

LOC100507513 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41468632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASE3	NM_002935.3	c.263G>A	p.Arg88His	missense_variant	2/2	ENST00000304639.4
LOC100507513	XR_110261.4	n.723-16206C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASE3	ENST00000304639.4	c.263G>A	p.Arg88His	missense_variant	2/2	1	NM_002935.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251328 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461612 Hom.: 0 Cov.: 48 AF XY: 0.00000413 AC XY: 3 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.263G>A (p.R88H) alteration is located in exon 2 (coding exon 1) of the RNASE3 gene. This alteration results from a G to A substitution at nucleotide position 263, causing the arginine (R) at amino acid position 88 to be replaced by a histidine (H). 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	0.17
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.15
Dann	Uncertain	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.22
Sift	Benign	0.092	T
Sift4G	Uncertain	0.060	T
Polyphen		0.98	D
Vest4		0.044
MutPred		0.53		Loss of MoRF binding (P = 0.0585);
MVP		0.56
MPC		0.14
ClinPred		0.25	T
GERP RS		0.31
Varity_R		0.078
gMVP		0.45

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: rs1372547752; hg19: chr14-21360108; COSMIC: COSV58959761;