6-166929611-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_003730.6(RNASET2):c.748C>T(p.Pro250Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. P250L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: RNASET2 NM_003730.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

Genes affected

RNASET2 (HGNC:21686): (ribonuclease T2) This ribonuclease gene is a novel member of the Rh/T2/S-glycoprotein class of extracellular ribonucleases. It is a single copy gene that maps to 6q27, a region associated with human malignancies and chromosomal rearrangement. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21073961).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000109 (16/1461888) while in subpopulation SAS AF= 0.000174 (15/86258). AF 95% confidence interval is 0.000107. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASET2	NM_003730.6	c.748C>T	p.Pro250Ser	missense_variant	9/9	ENST00000508775.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASET2	ENST00000508775.6	c.748C>T	p.Pro250Ser	missense_variant	9/9	1	NM_003730.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251454 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461888 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 727246

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: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cystic leukoencephalopathy without megalencephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Dec 03, 2018

The homozygous p.Pro250Ser variant in RNASET2 was identified by our study in one individual with cystic leukoencephalopathy without megalencephaly. The p.Pro250Ser variant in RNASET2 has not been previously reported in individuals with cystic leukoencephalopathy without megalencephaly and has been identified in 0.01949% (6/30782) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs759625896). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Pro250Ser variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.72	T;.;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-4.5	D;D;.;D;D
REVEL	Benign	0.13
Sift	Benign	0.10	T;T;.;T;D
Sift4G	Benign	0.10	T;T;T;T;.
Polyphen		0.99	.;D;.;D;.
Vest4		0.20
MutPred		0.45		.;Loss of catalytic residue at P250 (P = 0.0043);.;Loss of catalytic residue at P250 (P = 0.0043);Loss of catalytic residue at P250 (P = 0.0043);
MVP		0.70
MPC		0.52
ClinPred		0.78	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.68

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: rs759625896; hg19: chr6-167343099;