14-20801920-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002933.5(RNASE1):c.149G>T(p.Ser50Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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: -1.39

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20527756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASE1	NM_002933.5	c.149G>T	p.Ser50Ile	missense_variant	2/2	ENST00000397967.5
LOC105370397	XR_007064063.1	n.277-7919C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASE1	ENST00000397967.5	c.149G>T	p.Ser50Ile	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

Jan 24, 2023

The c.149G>T (p.S50I) 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 149, causing the serine (S) at amino acid position 50 to be replaced by an isoleucine (I). 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	0.29
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;T;T;T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.035	N
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Pathogenic	3.1	M;M;M;.;M
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		0.93	P;P;P;.;P
Vest4		0.18
MutPred		0.45		Gain of catalytic residue at S48 (P = 0.0065);Gain of catalytic residue at S48 (P = 0.0065);Gain of catalytic residue at S48 (P = 0.0065);.;Gain of catalytic residue at S48 (P = 0.0065);
MVP		0.69
MPC		0.56
ClinPred		0.93	D
GERP RS		-9.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.64

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: chr14-21270079;