14-20584315-T-C

Variant names:

• chr14-20584315-T-C
• rs200151964
• ENST00000432835.6:c.160A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145250.5(RNASE11):​c.160A>G​(p.Asn54Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,614,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N54S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: RNASE11 NM_145250.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

Genes affected

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]

ENSG00000259060 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.005972028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASE11	NM_001394189.1	c.160A>G	p.Asn54Asp	missense_variant	Exon 3 of 3		NP_001381118.1
RNASE11	NM_001394190.1	c.160A>G	p.Asn54Asp	missense_variant	Exon 3 of 3		NP_001381119.1
RNASE11	NM_001394191.1	c.160A>G	p.Asn54Asp	missense_variant	Exon 3 of 3		NP_001381120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASE11	ENST00000557105.6	c.160A>G	p.Asn54Asp	missense_variant	Exon 3 of 3	3		ENSP00000452412.2
ENSG00000259060	ENST00000555283.1	c.*25A>G		downstream_gene_variant		4		ENSP00000477006.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000398 AC: 100 AN: 251362 Hom.: 0 AF XY: 0.000375 AC XY: 51 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000261 AC: 381 AN: 1461848 Hom.: 0 Cov.: 33 AF XY: 0.000235 AC XY: 171 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00230

Gnomad4 NFE exome AF: 0.000206

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74512

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00216

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.000230

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.160A>G (p.N54D) alteration is located in exon 3 (coding exon 1) of the RNASE11 gene. This alteration results from a A to G substitution at nucleotide position 160, causing the asparagine (N) at amino acid position 54 to be replaced by an aspartic acid (D). 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	0.18
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.023	T;T;T;T;T;T;.;.;.;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.31	.;.;.;T;.;.;.;T;T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.0060	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;N;N;N;N;N;.;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N;N;N;.;N;N;N;N;D;D;D
REVEL	Benign	0.013
Sift	Benign	0.10	T;T;T;.;T;T;T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.11	B;B;B;B;B;B;.;.;.;.;.
Vest4		0.35
MVP		0.11
ClinPred		0.021	T
GERP RS		1.7
Varity_R		0.13
gMVP		0.47

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: rs200151964; hg19: chr14-21052474;