NM_001391974.1:c.449G>A

Variant names:

• chr10-133423233-C-T
• rs923535181
• NM_001391974.1:c.449G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001391974.1(SPRN):​c.449G>A​(p.Arg150Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000691 in 1,301,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: SPRN NM_001391974.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.53
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04042372).

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.449G>A	p.Arg150Gln	missense	Exon 2 of 2	NP_001378903.1	Q5BIV9
	SPRN	NM_001012508.6		c.449G>A	p.Arg150Gln	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.449G>A	p.Arg150Gln	missense	Exon 2 of 2	ENSP00000510252.1	Q5BIV9
	SPRN	ENST00000414069.2	TSL:1	c.449G>A	p.Arg150Gln	missense	Exon 2 of 2	ENSP00000433712.1	Q5BIV9
	SPRN	ENST00000949115.1		c.449G>A	p.Arg150Gln	missense	Exon 2 of 2	ENSP00000619174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000691 AC: 9 AN: 1301960 Hom.: 0 Cov.: 29 AF XY: 0.00000782 AC XY: 5 AN XY: 639338

African (AFR) AF: 0.00 AC: 0 AN: 26756

American (AMR) AF: 0.00 AC: 0 AN: 27762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21916

East Asian (EAS) AF: 0.00 AC: 0 AN: 29538

South Asian (SAS) AF: 0.00 AC: 0 AN: 69464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4564

European-Non Finnish (NFE) AF: 0.00000773 AC: 8 AN: 1035562

Other (OTH) AF: 0.0000186 AC: 1 AN: 53754

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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	0.086
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.3
DANN	Benign	0.97
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-2.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.011
Sift	Benign	0.14	T
Sift4G	Benign	0.52	T
Polyphen		0.0090	B
Vest4		0.068
MutPred		0.24		Loss of methylation at R150 (P = 0.0368)
MVP		0.030
ClinPred		0.067	T
GERP RS		-2.3
Varity_R		0.028
gMVP		0.0078
Mutation Taster		=96/4	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: rs923535181; hg19: chr10-135236737;