14-20556460-A-G

Variant names:

• chr14-20556460-A-G
• rs1243647
• NM_001110356.2:c.607T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001110356.2(RNASE9):​c.607T>C​(p.Ser203Pro) 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. 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 0.78 (46732 hom., cov: 32)
  • Exomes 𝑓: 0.78 (444111 hom.)
• Consequence: RNASE9 NM_001110356.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.228
• Publications: 36 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110356.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASE9	NM_001110356.2	MANE Select	c.607T>C	p.Ser203Pro	missense	Exon 3 of 3	NP_001103826.2
	RNASE9	NM_001110358.1		c.625T>C	p.Ser209Pro	missense	Exon 4 of 4	NP_001103828.1
	RNASE9	NM_001110359.1		c.625T>C	p.Ser209Pro	missense	Exon 5 of 5	NP_001103829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASE9	ENST00000554964.6	TSL:1 MANE Select	c.607T>C	p.Ser203Pro	missense	Exon 3 of 3	ENSP00000450599.2
	RNASE9	ENST00000404716.7	TSL:1	c.625T>C	p.Ser209Pro	missense	Exon 5 of 5	ENSP00000384683.3
	RNASE9	ENST00000553706.5	TSL:1	c.625T>C	p.Ser209Pro	missense	Exon 5 of 5	ENSP00000450570.1

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

GnomAD2 exomes AF: 0.766 AC: 190930 AN: 249292 AF XY: 0.772

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 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

African (AFR) AF: 0.798 AC: 26606 AN: 33340

American (AMR) AF: 0.660 AC: 29377 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.805 AC: 20875 AN: 25934

East Asian (EAS) AF: 0.679 AC: 26924 AN: 39628

South Asian (SAS) AF: 0.792 AC: 67928 AN: 85718

European-Finnish (FIN) AF: 0.811 AC: 43272 AN: 53324

Middle Eastern (MID) AF: 0.784 AC: 4497 AN: 5738

European-Non Finnish (NFE) AF: 0.787 AC: 865860 AN: 1100572

Other (OTH) AF: 0.787 AC: 47146 AN: 59904

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

African (AFR) AF: 0.800 AC: 33179 AN: 41496

American (AMR) AF: 0.714 AC: 10917 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.804 AC: 2791 AN: 3470

East Asian (EAS) AF: 0.668 AC: 3462 AN: 5180

South Asian (SAS) AF: 0.775 AC: 3738 AN: 4826

European-Finnish (FIN) AF: 0.806 AC: 8531 AN: 10588

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.792 AC: 53811 AN: 67978

Other (OTH) AF: 0.793 AC: 1673 AN: 2110

Alfa AF: 0.787 Hom.: 228160

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 v4.9

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
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00039	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-0.23
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.0080
Sift	Benign	1.0	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.069
MPC		0.10
ClinPred		0.00054	T
GERP RS		-1.1
Varity_R		0.047
gMVP		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1243647; hg19: chr14-21024619; COSMIC: COSV58880808;