14-20801971-G-A

Variant summary

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

The NM_002933.5(RNASE1):c.98C>T(p.Ala33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNASE1 NM_002933.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

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]

LOC105370397 (HGNC:):

ACMG classification

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
RNASE1	NM_002933.5	c.98C>T	p.Ala33Val	missense_variant	2/2	ENST00000397967.5
LOC105370397	XR_007064063.1	n.277-7868G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASE1	ENST00000397967.5	c.98C>T	p.Ala33Val	missense_variant	2/2	1	NM_002933.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jun 22, 2023

The c.98C>T (p.A33V) alteration is located in exon 3 (coding exon 1) of the RNASE1 gene. This alteration results from a C to T substitution at nucleotide position 98, causing the alanine (A) at amino acid position 33 to be replaced by a valine (V). 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	0.32
BayesDel_addAF	Benign	0.0068	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;T;T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.055
FATHMM_MKL	Benign	0.14	N
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.1	M;M;M;M
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Uncertain	0.45
Sift	Benign	0.046	D;D;D;D
Sift4G	Benign	0.20	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.28
MutPred		0.69		Gain of methylation at K34 (P = 0.0497);Gain of methylation at K34 (P = 0.0497);Gain of methylation at K34 (P = 0.0497);Gain of methylation at K34 (P = 0.0497);
MVP		0.85
MPC		0.23
ClinPred		0.94	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.29
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-21270130;