10-133423483-C-A

Variant names:

• chr10-133423483-C-A
• rs1018090673
• NM_001391974.1:c.199G>T

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.199G>T​(p.Ala67Ser) 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 1,012,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. A67T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: SPRN NM_001391974.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21250746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRN	NM_001391974.1	c.199G>T	p.Ala67Ser	missense_variant	Exon 2 of 2	ENST00000685335.1	NP_001378903.1
SPRN	NM_001012508.6	c.199G>T	p.Ala67Ser	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.199G>T	p.Ala67Ser	missense_variant	Exon 2 of 2		NM_001391974.1	ENSP00000510252.1
SPRN	ENST00000414069.2	c.199G>T	p.Ala67Ser	missense_variant	Exon 2 of 2	1		ENSP00000433712.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000395 AC: 4 AN: 1012772 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 482702

African (AFR) AF: 0.00 AC: 0 AN: 19964

American (AMR) AF: 0.00 AC: 0 AN: 5844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10554

East Asian (EAS) AF: 0.00 AC: 0 AN: 19558

South Asian (SAS) AF: 0.00 AC: 0 AN: 19284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2492

European-Non Finnish (NFE) AF: 0.00000454 AC: 4 AN: 880090

Other (OTH) AF: 0.00 AC: 0 AN: 38196

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.096
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.031	D
Polyphen		0.39	B
Vest4		0.37
MutPred		0.29		Gain of glycosylation at A67 (P = 0.0014);
MVP		0.13
ClinPred		0.87	D
GERP RS		3.2
Varity_R		0.14
gMVP		0.10
Mutation Taster		=100/0	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: rs1018090673; hg19: chr10-135236987;