14-20801816-C-A

Variant names:

• chr14-20801816-C-A
• rs200900834
• NM_002933.5:c.253G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002933.5(RNASE1):​c.253G>T​(p.Val85Phe) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V85I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNASE1 NM_002933.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• Publications: 0 publications found

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]

ENSG00000303743 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002933.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASE1	NM_002933.5	MANE Select	c.253G>T	p.Val85Phe	missense	Exon 2 of 2	NP_002924.1	P07998
	RNASE1	NM_198232.3		c.253G>T	p.Val85Phe	missense	Exon 2 of 2	NP_937875.1	P07998
	RNASE1	NM_198234.3		c.253G>T	p.Val85Phe	missense	Exon 3 of 3	NP_937877.1	P07998

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASE1	ENST00000397967.5	TSL:1 MANE Select	c.253G>T	p.Val85Phe	missense	Exon 2 of 2	ENSP00000381057.4	P07998
	RNASE1	ENST00000397970.4	TSL:1	c.253G>T	p.Val85Phe	missense	Exon 3 of 3	ENSP00000381060.4	P07998
	RNASE1	ENST00000340900.3	TSL:2	c.253G>T	p.Val85Phe	missense	Exon 3 of 3	ENSP00000344193.3	P07998

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.086	N
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	4.3	H
PhyloP100		-1.0
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.96	D
Vest4		0.61
MutPred		0.64		Gain of catalytic residue at F87 (P = 0.0149)
MVP		0.81
MPC		0.73
ClinPred		0.99	D
GERP RS		0.21
Varity_R		0.54
gMVP		0.81
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200900834; hg19: chr14-21269975;