chr14-20556460-A-G

Position:

• chr14-20556460-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000404716.7(RNASE9):​c.625T>C​(p.Ser209Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 1,600,838 control chromosomes in the GnomAD database, including 490,843 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.78 (46732 hom., cov: 32)
  • Exomes 𝑓: 0.78 (444111 hom.)
• 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2547378E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASE9	NM_001110356.2	c.607T>C	p.Ser203Pro	missense_variant	3/3	ENST00000554964.6	NP_001103826.2
RNASE9	NM_001001673.4	c.607T>C	p.Ser203Pro	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>C	p.Ser203Pro	missense_variant	3/3	1	NM_001110356.2	ENSP00000450599	P4

Frequencies

GnomAD3 genomes AF: 0.783 AC: 119000 AN: 152026 Hom.: 46688 Cov.: 32

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.850

Gnomad AMR AF: 0.714

Gnomad ASJ AF: 0.804

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.774

Gnomad FIN AF: 0.806

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.792

Gnomad OTH AF: 0.791

GnomAD3 exomes AF: 0.766 AC: 190930 AN: 249292 Hom.: 73648 AF XY: 0.772 AC XY: 103960 AN XY: 134644

Gnomad AFR exome AF: 0.796

Gnomad AMR exome AF: 0.650

Gnomad ASJ exome AF: 0.803

Gnomad EAS exome AF: 0.659

Gnomad SAS exome AF: 0.797

Gnomad FIN exome AF: 0.806

Gnomad NFE exome AF: 0.794

Gnomad OTH exome AF: 0.780

GnomAD4 exome AF: 0.782 AC: 1132485 AN: 1448694 Hom.: 444111 Cov.: 31 AF XY: 0.783 AC XY: 564435 AN XY: 721120

Gnomad4 AFR exome AF: 0.798

Gnomad4 AMR exome AF: 0.660

Gnomad4 ASJ exome AF: 0.805

Gnomad4 EAS exome AF: 0.679

Gnomad4 SAS exome AF: 0.792

Gnomad4 FIN exome AF: 0.811

Gnomad4 NFE exome AF: 0.787

Gnomad4 OTH exome AF: 0.787

GnomAD4 genome AF: 0.783 AC: 119096 AN: 152144 Hom.: 46732 Cov.: 32 AF XY: 0.781 AC XY: 58068 AN XY: 74378

Gnomad4 AFR AF: 0.800

Gnomad4 AMR AF: 0.714

Gnomad4 ASJ AF: 0.804

Gnomad4 EAS AF: 0.668

Gnomad4 SAS AF: 0.775

Gnomad4 FIN AF: 0.806

Gnomad4 NFE AF: 0.792

Gnomad4 OTH AF: 0.793

Alfa AF: 0.787 Hom.: 122424

Bravo AF: 0.774

TwinsUK AF: 0.779 AC: 2888

ALSPAC AF: 0.788 AC: 3036

ESP6500AA AF: 0.797 AC: 3512

ESP6500EA AF: 0.793 AC: 6820

ExAC AF: 0.772 AC: 93765

Asia WGS AF: 0.721 AC: 2511 AN: 3478

EpiCase AF: 0.802

EpiControl AF: 0.798

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.072
DEOGEN2	Benign	0.0011	T;T;T;T;.;.;T;T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00039	N
LIST_S2	Benign	0.21	.;.;.;.;.;.;.;T;.;.;T
MetaRNN	Benign	0.0000013	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.81	N;N;N;N;.;.;N;N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.43	N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.0080
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.32	T;T;T;T;.;.;T;T;.;.;.
Polyphen		0.0	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.069
MPC		0.10
ClinPred		0.00054	T
GERP RS		-1.1
Varity_R		0.047
gMVP		0.31

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; COSMIC: COSV58880808;