NM_006307.5:c.831C>A

Variant names:

• chrX-38160141-G-T
• rs377733865
• NM_006307.5:c.831C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006307.5(SRPX):​c.831C>A​(p.Ser277Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,210,370 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SRPX NM_006307.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.231
• Publications: 1 publications found

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]

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006307.5. 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
	SRPX	NM_006307.5	MANE Select	c.831C>A	p.Ser277Arg	missense	Exon 7 of 10	NP_006298.1	P78539-1
	SRPX	NM_001170750.2		c.771C>A	p.Ser257Arg	missense	Exon 6 of 9	NP_001164221.1	P78539-5
	SRPX	NM_001170751.2		c.654C>A	p.Ser218Arg	missense	Exon 6 of 9	NP_001164222.1	P78539-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRPX	ENST00000378533.4	TSL:1 MANE Select	c.831C>A	p.Ser277Arg	missense	Exon 7 of 10	ENSP00000367794.3	P78539-1
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-505980G>T		intron	N/A	ENSP00000417050.1	B4E171
	SRPX	ENST00000898757.1		c.831C>A	p.Ser277Arg	missense	Exon 7 of 11	ENSP00000568816.1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112339 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000940

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182926 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098031 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363389

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 54095

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4133

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842003

Other (OTH) AF: 0.00 AC: 0 AN: 46091

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112339 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34487

African (AFR) AF: 0.00 AC: 0 AN: 30896

American (AMR) AF: 0.0000940 AC: 1 AN: 10634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 2700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6183

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53248

Other (OTH) AF: 0.00 AC: 0 AN: 1523

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.23
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.38
MutPred		0.56		Loss of catalytic residue at S277 (P = 0.0782)
MVP		0.85
MPC		0.15
ClinPred		0.94	D
GERP RS		-3.9
Varity_R		0.81
gMVP		0.66
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs377733865; hg19: chrX-38019394;