Genetic Variant SPRN:p.Ala67Thr (chr10-133423483-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001391974.1(SPRN):c.199G>A(p.Ala67Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPRN
NM_001391974.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.1832911).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRN	NM_001391974.1 link	c.199G>A	p.Ala67Thr	missense_variant	Exon 2 of 2	ENST00000685335.1	NP_001378903.1
SPRN	NM_001012508.6 link	c.199G>A	p.Ala67Thr	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.199G>A	p.Ala67Thr	missense_variant	Exon 2 of 2		NM_001391974.1	ENSP00000510252.1		Q5BIV9
SPRN	ENST00000414069.2 link	c.199G>A	p.Ala67Thr	missense_variant	Exon 2 of 2	1		ENSP00000433712.1		Q5BIV9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

890

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1012772

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

482702

African (AFR)

AF:

0.00

AC:

AN:

19964

American (AMR)

AF:

0.00

AC:

AN:

5844

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10554

East Asian (EAS)

AF:

0.00

AC:

AN:

19558

South Asian (SAS)

AF:

0.00

AC:

AN:

19284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2492

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

880090

Other (OTH)

AF:

0.00

AC:

AN:

38196

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 25, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.199G>A (p.A67T) alteration is located in exon 2 (coding exon 1) of the SPRN gene. This alteration results from a G to A substitution at nucleotide position 199, causing the alanine (A) at amino acid position 67 to be replaced by a threonine (T). 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

Uncertain

0.34

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.094

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.5

PhyloP100

1.3

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.090

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.010

Polyphen

0.017

Vest4

0.42

MutPred

0.29

Gain of glycosylation at A67 (P = 0.0176);

MVP

0.17

ClinPred

0.86

GERP RS

3.2

Varity_R

0.22

gMVP

0.15

Mutation Taster

=96/4

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over