Variant X-38160947-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_006307.5(SRPX):c.761G>C(p.Arg254Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 1,207,160 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000028 ( 0 hom. 8 hem. )

Consequence

SRPX
NM_006307.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.15

Variant links:

Genes affected

SRPX (HGNC:11309): (sushi repeat containing protein X-linked) Predicted to be an extracellular matrix structural constituent. Predicted to be involved in cell adhesion. Predicted to act upstream of or within several processes, including negative regulation of cell proliferation involved in contact inhibition; phagolysosome assembly; and positive regulation of extrinsic apoptotic signaling pathway in absence of ligand. Part of collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

SRPX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33153266).

BS2

High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRPX	NM_006307.5 linkuse as main transcript	c.761G>C	p.Arg254Pro	missense_variant	6/10	ENST00000378533.4	NP_006298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRPX	ENST00000378533.4 linkuse as main transcript	c.761G>C	p.Arg254Pro	missense_variant	6/10	1	NM_006307.5	ENSP00000367794	P2	P78539-1
SRPX	ENST00000544439.5 linkuse as main transcript	c.701G>C	p.Arg234Pro	missense_variant	5/9	2		ENSP00000440758	A2	P78539-5
SRPX	ENST00000432886.6 linkuse as main transcript	c.584G>C	p.Arg195Pro	missense_variant	5/9	2		ENSP00000411165		P78539-3
SRPX	ENST00000538295.5 linkuse as main transcript	c.761G>C	p.Arg254Pro	missense_variant	6/9	2		ENSP00000445034		P78539-4

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111465

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33657

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000548

AC:

AN:

182587

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67083

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000283

AC:

AN:

1095695

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

361219

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

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:

0.0000321

Gnomad4 OTH exome

AF:

0.0000652

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111465

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33657

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

The c.761G>C (p.R254P) alteration is located in exon 6 (coding exon 6) of the SRPX gene. This alteration results from a G to C substitution at nucleotide position 761, causing the arginine (R) at amino acid position 254 to be replaced by a proline (P). 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

0.38

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.036

.;.;.;T

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.33

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

.;.;L;L

MutationTaster

Benign

0.98

N;N;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.21

T;T;T;T

Sift4G

Benign

0.32

T;T;T;T

Polyphen

0.74

.;.;.;P

Vest4

0.54

MutPred

0.61

.;.;Loss of MoRF binding (P = 0.0165);Loss of MoRF binding (P = 0.0165);

MVP

0.97

MPC

0.076

ClinPred

0.43

GERP RS

3.9

Varity_R

0.67

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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