Genetic Variant SPRN:p.Pro60Leu (chr10-133423503-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001391974.1(SPRN):c.179C>T(p.Pro60Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,170,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P60A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000039 ( 0 hom. )

Consequence

SPRN
NM_001391974.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.413

Variant links:

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]

SPRN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.050333798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRN	NM_001391974.1 link	c.179C>T	p.Pro60Leu	missense_variant	Exon 2 of 2	ENST00000685335.1	NP_001378903.1
SPRN	NM_001012508.6 link	c.179C>T	p.Pro60Leu	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 link	c.179C>T	p.Pro60Leu	missense_variant	Exon 2 of 2		NM_001391974.1	ENSP00000510252.1		Q5BIV9
SPRN	ENST00000414069.2 link	c.179C>T	p.Pro60Leu	missense_variant	Exon 2 of 2	1		ENSP00000433712.1		Q5BIV9

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

147862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000600

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000391

AC:

AN:

1022614

Hom.:

Cov.:

AF XY:

0.00000206

AC XY:

AN XY:

486358

show subpopulations

Gnomad4 AFR exome

AF:

0.0000984

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:

0.00000226

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000108

AC:

AN:

147968

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

72140

show subpopulations

Gnomad4 AFR

AF:

0.000293

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000600

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000125

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.179C>T (p.P60L) alteration is located in exon 2 (coding exon 1) of the SPRN gene. This alteration results from a C to T substitution at nucleotide position 179, causing the proline (P) at amino acid position 60 to be replaced by a leucine (L). 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

0.17

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0050

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.50

M_CAP

Benign

0.0068

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.2

REVEL

Benign

0.015

Sift

Uncertain

0.021

Sift4G

Benign

0.25

Polyphen

0.11

Vest4

0.085

MutPred

0.20

Loss of relative solvent accessibility (P = 0.0186);

MVP

0.048

ClinPred

0.15

GERP RS

2.8

Varity_R

0.052

gMVP

0.073

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over