10-133423474-C-A

Variant names:

• chr10-133423474-C-A
• rs1431961849
• NM_001391974.1:c.208G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001391974.1(SPRN):​c.208G>T​(p.Gly70Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000395 in 1,012,620 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: 0.0000040 (0 hom.)
• Consequence: SPRN NM_001391974.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.992
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31970972).

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.208G>T	p.Gly70Trp	missense	Exon 2 of 2	NP_001378903.1	Q5BIV9
	SPRN	NM_001012508.6		c.208G>T	p.Gly70Trp	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.208G>T	p.Gly70Trp	missense	Exon 2 of 2	ENSP00000510252.1	Q5BIV9
	SPRN	ENST00000414069.2	TSL:1	c.208G>T	p.Gly70Trp	missense	Exon 2 of 2	ENSP00000433712.1	Q5BIV9
	SPRN	ENST00000949115.1		c.208G>T	p.Gly70Trp	missense	Exon 2 of 2	ENSP00000619174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000395 AC: 4 AN: 1012620 Hom.: 0 Cov.: 28 AF XY: 0.00000621 AC XY: 3 AN XY: 482710

African (AFR) AF: 0.00 AC: 0 AN: 19916

American (AMR) AF: 0.00 AC: 0 AN: 5834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10556

East Asian (EAS) AF: 0.00 AC: 0 AN: 19518

South Asian (SAS) AF: 0.00 AC: 0 AN: 19328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16830

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

European-Non Finnish (NFE) AF: 0.00000455 AC: 4 AN: 879956

Other (OTH) AF: 0.00 AC: 0 AN: 38174

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	0.68
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.99
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.098
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.49		Gain of MoRF binding (P = 0.0187)
MVP		0.34
ClinPred		0.91	D
GERP RS		1.3
Varity_R		0.32
gMVP		0.15
Mutation Taster		=97/3	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: rs1431961849; hg19: chr10-135236978;