Genetic Variant SPRN:p.Glu103Lys (chr10-133423375-C-T) – 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.307G>A(p.Glu103Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 1,355,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. E103A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SPRN
NM_001391974.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

Publications

0 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=0.045648396).

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.307G>A	p.Glu103Lys	missense	Exon 2 of 2	NP_001378903.1	Q5BIV9
	SPRN	NM_001012508.6		c.307G>A	p.Glu103Lys	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.307G>A	p.Glu103Lys	missense	Exon 2 of 2	ENSP00000510252.1	Q5BIV9
SPRN	ENST00000414069.2	TSL:1	c.307G>A	p.Glu103Lys	missense	Exon 2 of 2	ENSP00000433712.1	Q5BIV9
SPRN	ENST00000949115.1		c.307G>A	p.Glu103Lys	missense	Exon 2 of 2	ENSP00000619174.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000190

AC:

AN:

105468

AF XY:

0.0000170

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000513

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000177

AC:

AN:

1355864

Hom.:

Cov.:

AF XY:

0.0000120

AC XY:

AN XY:

669134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28036

American (AMR)

AF:

0.00

AC:

AN:

33246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24244

East Asian (EAS)

AF:

0.00

AC:

AN:

31980

South Asian (SAS)

AF:

0.00

AC:

AN:

76204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35464

Middle Eastern (MID)

AF:

0.000223

AC:

AN:

4484

European-Non Finnish (NFE)

AF:

0.0000197

AC:

AN:

1065690

Other (OTH)

AF:

0.0000354

AC:

AN:

56516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.022

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.77

M_CAP

Benign

0.029

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

1.5

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.1

REVEL

Benign

0.057

Sift

Benign

0.29

Sift4G

Benign

0.79

Polyphen

0.0010

Vest4

0.11

MutPred

0.23

Gain of ubiquitination at E103 (P = 0.0029)

MVP

0.030

ClinPred

0.039

GERP RS

-0.41

Varity_R

0.062

gMVP

0.075

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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