Genetic Variant SPRN:p.Pro60Arg (chr10-133423503-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001391974.1(SPRN):c.179C>G(p.Pro60Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 147,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P60L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPRN
NM_001391974.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.413

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06751129).

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.179C>G	p.Pro60Arg	missense	Exon 2 of 2	NP_001378903.1	Q5BIV9
	SPRN	NM_001012508.6		c.179C>G	p.Pro60Arg	missense	Exon 2 of 2	NP_001012526.2	Q5BIV9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPRN	ENST00000685335.1	MANE Select	c.179C>G	p.Pro60Arg	missense	Exon 2 of 2	ENSP00000510252.1	Q5BIV9
SPRN	ENST00000414069.2	TSL:1	c.179C>G	p.Pro60Arg	missense	Exon 2 of 2	ENSP00000433712.1	Q5BIV9
SPRN	ENST00000949115.1		c.179C>G	p.Pro60Arg	missense	Exon 2 of 2	ENSP00000619174.1

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

147862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000300

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1022614

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

486358

African (AFR)

AF:

0.00

AC:

AN:

20330

American (AMR)

AF:

0.00

AC:

AN:

6162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11080

East Asian (EAS)

AF:

0.00

AC:

AN:

20694

South Asian (SAS)

AF:

0.00

AC:

AN:

19368

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2576

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

885794

Other (OTH)

AF:

0.00

AC:

AN:

38858

GnomAD4 genome

AF:

0.0000135

AC:

AN:

147862

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

72024

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40802

American (AMR)

AF:

0.00

AC:

AN:

14860

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

4958

South Asian (SAS)

AF:

0.00

AC:

AN:

4616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000300

AC:

AN:

66666

Other (OTH)

AF:

0.00

AC:

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0049

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.0078

LIST_S2

Benign

0.38

M_CAP

Benign

0.0056

MetaRNN

Benign

0.068

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

0.41

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.92

REVEL

Benign

0.031

Sift

Uncertain

0.016

Sift4G

Benign

0.62

Polyphen

0.010

Vest4

0.065

MutPred

0.26

Gain of methylation at P60 (P = 0.004)

MVP

0.030

ClinPred

0.12

GERP RS

2.8

Varity_R

0.067

gMVP

0.049

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over