10-133423413-C-T

Variant names:

• chr10-133423413-C-T
• rs370469630
• NM_001391974.1:c.269G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 14/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008900732).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001391974.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRN	NM_001391974.1	MANE Select	c.269G>A	p.Arg90Lys	missense	Exon 2 of 2	NP_001378903.1	Q5BIV9
	SPRN	NM_001012508.6		c.269G>A	p.Arg90Lys	missense	Exon 2 of 2	NP_001012526.2	Q5BIV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRN	ENST00000685335.1	MANE Select	c.269G>A	p.Arg90Lys	missense	Exon 2 of 2	ENSP00000510252.1	Q5BIV9
	SPRN	ENST00000414069.2	TSL:1	c.269G>A	p.Arg90Lys	missense	Exon 2 of 2	ENSP00000433712.1	Q5BIV9
	SPRN	ENST00000949115.1		c.269G>A	p.Arg90Lys	missense	Exon 2 of 2	ENSP00000619174.1

Frequencies

GnomAD3 genomes AF: 0.000233 AC: 35 AN: 150522 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000307 AC: 24 AN: 78102 AF XY: 0.000334

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 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.: 4 Cov.: 29 AF XY: 0.000138 AC XY: 87 AN XY: 628360

African (AFR) AF: 0.0000378 AC: 1 AN: 26478

American (AMR) AF: 0.0000382 AC: 1 AN: 26174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22224

East Asian (EAS) AF: 0.00136 AC: 38 AN: 27878

South Asian (SAS) AF: 0.0000154 AC: 1 AN: 64990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3686

European-Non Finnish (NFE) AF: 0.00000686 AC: 7 AN: 1021072

Other (OTH) AF: 0.00273 AC: 142 AN: 52032

GnomAD4 genome AF: 0.000239 AC: 36 AN: 150630 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 9 AN XY: 73582

African (AFR) AF: 0.0000968 AC: 4 AN: 41342

American (AMR) AF: 0.000725 AC: 11 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00274 AC: 14 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000101 AC: 1 AN: 9912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67500

Other (OTH) AF: 0.00239 AC: 5 AN: 2096

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000238

ExAC AF: 0.0000702 AC: 1

Asia WGS AF: 0.00789 AC: 27 AN: 3436

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.062
Sift	Benign	0.044	D
Sift4G	Benign	0.68	T
Polyphen		0.79	P
Vest4		0.16
MutPred		0.29		Gain of glycosylation at R90 (P = 0.0138)
MVP		0.055
ClinPred		0.033	T
GERP RS		3.3
Varity_R		0.26
gMVP		0.11
Mutation Taster		=99/1	polymorphism

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: rs370469630; hg19: chr10-135236917; COSMIC: COSV100448781; COSMIC: COSV100448781;