Genetic Variant SPRN:p.Arg90Lys (chr10-133423413-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001391974.1(SPRN):c.269G>A(p.Arg90Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,426,468 control chromosomes in the GnomAD database, including 4 homozygotes. 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 (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 4 hom. )

Consequence

SPRN
NM_001391974.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

Variant links:

Genes affected

SPRN (HGNC:16871): (shadow of prion protein) Predicted to enable nucleic acid binding activity. Predicted to be involved in protein import into nucleus. Predicted to be located in membrane. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SPRN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008900732).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRN	NM_001391974.1 link	c.269G>A	p.Arg90Lys	missense_variant	Exon 2 of 2	ENST00000685335.1	NP_001378903.1
SPRN	NM_001012508.6 link	c.269G>A	p.Arg90Lys	missense_variant	Exon 2 of 2		NP_001012526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRN	ENST00000685335.1 link	c.269G>A	p.Arg90Lys	missense_variant	Exon 2 of 2		NM_001391974.1	ENSP00000510252.1		Q5BIV9
SPRN	ENST00000414069.2 link	c.269G>A	p.Arg90Lys	missense_variant	Exon 2 of 2	1		ENSP00000433712.1		Q5BIV9

Frequencies

GnomAD3 genomes

AF:

0.000233

AC:

AN:

150522

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000970

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000726

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00273

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000101

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00193

GnomAD3 exomes

AF:

0.000307

AC:

AN:

78102

Hom.:

AF XY:

0.000334

AC XY:

AN XY:

44856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000650

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00757

Gnomad SAS exome

AF:

0.0000591

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000449

GnomAD4 exome

AF:

0.000149

AC:

190

AN:

1275838

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

628360

show subpopulations

Gnomad4 AFR exome

AF:

0.0000378

Gnomad4 AMR exome

AF:

0.0000382

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00136

Gnomad4 SAS exome

AF:

0.0000154

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000686

Gnomad4 OTH exome

AF:

0.00273

GnomAD4 genome

AF:

0.000239

AC:

AN:

150630

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

73582

show subpopulations

Gnomad4 AFR

AF:

0.0000968

Gnomad4 AMR

AF:

0.000725

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00274

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000101

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00239

Alfa

AF:

0.000253

Hom.:

Bravo

AF:

0.000238

ExAC

AF:

0.0000702

AC:

Asia WGS

AF:

0.00789

AC:

AN:

3436

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.269G>A (p.R90K) alteration is located in exon 2 (coding exon 1) of the SPRN gene. This alteration results from a G to A substitution at nucleotide position 269, causing the arginine (R) at amino acid position 90 to be replaced by a lysine (K). 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

0.17

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.070

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.6

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-2.2

REVEL

Benign

0.062

Sift

Benign

0.044

Sift4G

Benign

0.68

Polyphen

0.79

Vest4

0.16

MutPred

0.29

Gain of glycosylation at R90 (P = 0.0138);

MVP

0.055

ClinPred

0.033

GERP RS

3.3

Varity_R

0.26

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over