14-20590468-C-A

Variant names:

• chr14-20590468-C-A
• NM_001024822.4:c.256G>T

Variant summary

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

The NM_001024822.4(RNASE12):​c.256G>T​(p.Val86Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RNASE12 NM_001024822.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.25

Genes affected

RNASE12 (HGNC:24211): (ribonuclease A family member 12 (inactive)) Predicted to enable nucleic acid binding activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000259060 (HGNC:):

RNASE11 (HGNC:19269): (ribonuclease A family member 11 (inactive)) Predicted to enable endonuclease activity and nucleic acid binding activity. Predicted to be involved in nucleic acid phosphodiester bond hydrolysis. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

RNASE11-AS1 (HGNC:27381): (RNASE11 and RNASE12 antisense RNA 1)

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=0.1767075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASE12	NM_001024822.4	c.256G>T	p.Val86Phe	missense_variant	Exon 2 of 2	ENST00000696784.1	NP_001019993.1
RNASE11-AS1	NR_122043.1	n.127C>A		non_coding_transcript_exon_variant	Exon 2 of 5
RNASE11	NM_145250.5	c.-394G>T		upstream_gene_variant			NP_660293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASE12	ENST00000696784.1	c.256G>T	p.Val86Phe	missense_variant	Exon 2 of 2		NM_001024822.4	ENSP00000512867.1
ENSG00000259060	ENST00000555283.1	c.131+125G>T		intron_variant	Intron 2 of 2	4		ENSP00000477006.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.256G>T (p.V86F) alteration is located in exon 1 (coding exon 1) of the RNASE12 gene. This alteration results from a G to T substitution at nucleotide position 256, causing the valine (V) at amino acid position 86 to be replaced by a phenylalanine (F). 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	0.10
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.24	T
Polyphen		0.85	P
Vest4		0.27
MutPred		0.52		Gain of catalytic residue at K84 (P = 0);
MVP		0.20
MPC		0.015
ClinPred		0.99	D
GERP RS		-3.6
Varity_R		0.24
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr14-21058627;