chr10-133423233-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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. 15/21 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

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

Verdict is Likely_benign. Variant got -2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRN	NM_001391974.1	c.449G>A	p.Arg150Gln	missense_variant	Exon 2 of 2	ENST00000685335.1	NP_001378903.1
SPRN	NM_001012508.6	c.449G>A	p.Arg150Gln	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	c.449G>A	p.Arg150Gln	missense_variant	Exon 2 of 2		NM_001391974.1	ENSP00000510252.1
SPRN	ENST00000414069.2	c.449G>A	p.Arg150Gln	missense_variant	Exon 2 of 2	1		ENSP00000433712.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000773

Gnomad4 OTH exome AF: 0.0000186

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.449G>A (p.R150Q) 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 449, causing the arginine (R) at amino acid position 150 to be replaced by a glutamine (Q). 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	0.086
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
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

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

Other links and lift over

dbSNP: rs923535181; hg19: chr10-135236737;