rs1243647

Positions:

• chr14-20556460-A-C
• chr14-20556460-A-G

Variant summary

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

The ENST00000404716.7(RNASE9):​c.625T>G​(p.Ser209Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RNASE9 ENST00000404716.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.228

Genes affected

RNASE9 (HGNC:20673): (ribonuclease A family member 9 (inactive)) Predicted to enable nucleic acid binding activity. Predicted to act upstream of or within positive regulation of flagellated sperm motility involved in capacitation. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

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=0.04893014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASE9	NM_001110356.2	c.607T>G	p.Ser203Ala	missense_variant	3/3	ENST00000554964.6	NP_001103826.2
RNASE9	NM_001001673.4	c.607T>G	p.Ser203Ala	missense_variant	2/2		NP_001001673.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASE9	ENST00000554964.6	c.607T>G	p.Ser203Ala	missense_variant	3/3	1	NM_001110356.2	ENSP00000450599	P4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.14
DANN	Benign	0.72
DEOGEN2	Benign	0.00062	T;T;T;T;.;.;T;T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.13	.;.;.;.;.;.;.;T;.;.;T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.049	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;N;.;.;N;N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.0	N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.0040
Sift	Benign	0.39	T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	1.0	T;T;T;T;.;.;T;T;.;.;.
Polyphen		0.0	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.11
MutPred		0.31		Gain of catalytic residue at S204 (P = 0.0014);Gain of catalytic residue at S204 (P = 0.0014);Gain of catalytic residue at S204 (P = 0.0014);Gain of catalytic residue at S204 (P = 0.0014);.;.;Gain of catalytic residue at S204 (P = 0.0014);Gain of catalytic residue at S204 (P = 0.0014);.;.;.;
MVP		0.11
MPC		0.070
ClinPred		0.058	T
GERP RS		-1.1
Varity_R		0.037
gMVP		0.12

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: rs1243647; hg19: chr14-21024619;