14-20801947-A-G

Variant names:

• chr14-20801947-A-G
• rs1368258725
• NM_002933.5:c.122T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002933.5(RNASE1):​c.122T>C​(p.Met41Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RNASE1 NM_002933.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASE1	NM_002933.5	c.122T>C	p.Met41Thr	missense_variant	Exon 2 of 2	ENST00000397967.5	NP_002924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASE1	ENST00000397967.5	c.122T>C	p.Met41Thr	missense_variant	Exon 2 of 2	1	NM_002933.5	ENSP00000381057.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39692

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86258

Gnomad4 FIN exome AF: 0.0000187 AC: 1 AN: 53378

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1111952

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.000224 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.122T>C (p.M41T) alteration is located in exon 3 (coding exon 1) of the RNASE1 gene. This alteration results from a T to C substitution at nucleotide position 122, causing the methionine (M) at amino acid position 41 to be replaced by a threonine (T). 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	Uncertain	0.50
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;T;T;T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	.;.;.;D;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.2	M;M;M;.;M
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.019	D;D;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D;D
Polyphen		0.92	P;P;P;.;P
Vest4		0.38
MutPred		0.64		Gain of phosphorylation at M41 (P = 0.0094);Gain of phosphorylation at M41 (P = 0.0094);Gain of phosphorylation at M41 (P = 0.0094);.;Gain of phosphorylation at M41 (P = 0.0094);
MVP		0.92
MPC		0.74
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.60
gMVP		0.39
Mutation Taster		=89/111	disease causing

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

Other links and lift over

dbSNP: rs1368258725; hg19: chr14-21270106;