Genetic Variant SSPN:p.Ala144Thr (chr12-26230774-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005086.5(SSPN):c.430G>A(p.Ala144Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000545 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

SSPN
NM_005086.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.16

Variant links:

Genes affected

SSPN (HGNC:11322): (sarcospan) This gene encodes a member of the dystrophin-glycoprotein complex (DGC). The DGC spans the sarcolemma and is comprised of dystrophin, syntrophin, alpha- and beta-dystroglycans and sarcoglycans. The DGC provides a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. Two alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Oct 2008]

SSPN links:

ENSG00000255750 (HGNC:):

ENSG00000255750 links:

ITPR2-AS1 (HGNC:56072): (ITPR2 and SSPN antisense RNA 1)

ITPR2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19861594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSPN	NM_005086.5 link	c.430G>A	p.Ala144Thr	missense_variant	Exon 3 of 3	ENST00000242729.7	NP_005077.2	Q14714-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSPN	ENST00000242729.7 link	c.430G>A	p.Ala144Thr	missense_variant	Exon 3 of 3	1	NM_005086.5	ENSP00000242729.2		Q14714-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152176

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251318

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000620

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000818

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.430G>A (p.A144T) alteration is located in exon 3 (coding exon 3) of the SSPN gene. This alteration results from a G to A substitution at nucleotide position 430, causing the alanine (A) at amino acid position 144 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

Benign

0.093

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0080

T;.;.;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.86

D;.;D;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

.;.;.;L

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-2.8

D;D;D;N

REVEL

Benign

0.21

Sift

Uncertain

0.016

D;D;D;T

Sift4G

Uncertain

0.024

D;D;D;D

Polyphen

1.0

.;.;.;D

Vest4

0.22, 0.20, 0.20

MutPred

0.53

.;.;.;Gain of glycosylation at A144 (P = 0.0379);

MVP

0.21

MPC

1.3

ClinPred

0.53

GERP RS

4.8

Varity_R

0.12

gMVP

0.68

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