NM_001391974.1:c.209G>C

Variant names:

• chr10-133423473-C-G
• rs888299083
• NM_001391974.1:c.209G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001391974.1(SPRN):​c.209G>C​(p.Gly70Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,160,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G70R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: SPRN NM_001391974.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0830
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043070197).

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.209G>C	p.Gly70Ala	missense	Exon 2 of 2	NP_001378903.1	Q5BIV9
	SPRN	NM_001012508.6		c.209G>C	p.Gly70Ala	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.209G>C	p.Gly70Ala	missense	Exon 2 of 2	ENSP00000510252.1	Q5BIV9
	SPRN	ENST00000414069.2	TSL:1	c.209G>C	p.Gly70Ala	missense	Exon 2 of 2	ENSP00000433712.1	Q5BIV9
	SPRN	ENST00000949115.1		c.209G>C	p.Gly70Ala	missense	Exon 2 of 2	ENSP00000619174.1

Frequencies

GnomAD3 genomes AF: 0.000351 AC: 52 AN: 148070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.000979

GnomAD4 exome AF: 0.0000642 AC: 65 AN: 1012188 Hom.: 0 Cov.: 28 AF XY: 0.0000746 AC XY: 36 AN XY: 482450

African (AFR) AF: 0.000803 AC: 16 AN: 19922

American (AMR) AF: 0.000344 AC: 2 AN: 5820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10552

East Asian (EAS) AF: 0.000102 AC: 2 AN: 19516

South Asian (SAS) AF: 0.00 AC: 0 AN: 19324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2508

European-Non Finnish (NFE) AF: 0.0000477 AC: 42 AN: 879596

Other (OTH) AF: 0.0000787 AC: 3 AN: 38140

GnomAD4 genome AF: 0.000351 AC: 52 AN: 148178 Hom.: 0 Cov.: 32 AF XY: 0.000332 AC XY: 24 AN XY: 72248

African (AFR) AF: 0.00112 AC: 46 AN: 41046

American (AMR) AF: 0.000134 AC: 2 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4960

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66596

Other (OTH) AF: 0.000969 AC: 2 AN: 2064

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000317

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	0.11
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.6
DANN	Benign	0.62
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.66	N
PhyloP100		0.083
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.078
Sift	Benign	1.0	T
Sift4G	Benign	0.22	T
Polyphen		0.015	B
Vest4		0.21
MutPred		0.51		Loss of catalytic residue at G70 (P = 0.0099)
MVP		0.014
ClinPred		0.042	T
GERP RS		1.5
Varity_R		0.12
gMVP		0.072
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: rs888299083; hg19: chr10-135236977;