10-133423473-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001391974.1(SPRN):​c.209G>A​(p.Gly70Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000988 in 1,012,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)
  • Exomes 𝑓: 9.9e-7 (0 hom.)
• Consequence: SPRN NM_001391974.1 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21941653).

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>A	p.Gly70Glu	missense	Exon 2 of 2	NP_001378903.1	Q5BIV9
	SPRN	NM_001012508.6		c.209G>A	p.Gly70Glu	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>A	p.Gly70Glu	missense	Exon 2 of 2	ENSP00000510252.1	Q5BIV9
	SPRN	ENST00000414069.2	TSL:1	c.209G>A	p.Gly70Glu	missense	Exon 2 of 2	ENSP00000433712.1	Q5BIV9
	SPRN	ENST00000949115.1		c.209G>A	p.Gly70Glu	missense	Exon 2 of 2	ENSP00000619174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.88e-7 AC: 1 AN: 1012188 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 482450

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19922

American (AMR) AF: 0.00 AC: 0 AN: 5820

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

East Asian (EAS) AF: 0.00 AC: 0 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: 0.00000114 AC: 1 AN: 879596

Other (OTH) AF: 0.00 AC: 0 AN: 38140

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.083
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.086
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.94	P
Vest4		0.28
MutPred		0.33		Gain of solvent accessibility (P = 0.0411)
MVP		0.10
ClinPred		0.89	D
GERP RS		1.5
Varity_R		0.48
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: rs888299083; hg19: chr10-135236977; COSMIC: COSV105168784; COSMIC: COSV105168784;