11-126265065-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_003139.4(SRPRA):c.1419T>G(p.Ser473Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: SRPRA NM_003139.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

Genes affected

SRPRA (HGNC:11307): (SRP receptor subunit alpha) The gene encodes a subunit of the endoplasmic reticulum signal recognition particle receptor that, in conjunction with the signal recognition particle, is involved in the targeting and translocation of signal sequence tagged secretory and membrane proteins across the endoplasmic reticulum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity SRPRA_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.080212474).
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRPRA	NM_003139.4	c.1419T>G	p.Ser473Arg	missense_variant	11/14	ENST00000332118.11
SRPRA	NM_001177842.2	c.1335T>G	p.Ser445Arg	missense_variant	10/13
SRPRA	XM_047427497.1	c.1419T>G	p.Ser473Arg	missense_variant	11/14
SRPRA	XM_017018179.3	c.1419T>G	p.Ser473Arg	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRPRA	ENST00000332118.11	c.1419T>G	p.Ser473Arg	missense_variant	11/14	1	NM_003139.4	P1
SRPRA	ENST00000532259.1	c.1335T>G	p.Ser445Arg	missense_variant	10/13	2
SRPRA	ENST00000531104.1	n.498T>G		non_coding_transcript_exon_variant	2/2	2
SRPRA	ENST00000527817.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152198 Hom.: 0 Cov.: 33

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000994 AC: 25 AN: 251398 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135888

Gnomad AFR exome AF: 0.0000615

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: 0.000139

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.0000866 AC XY: 63 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

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: 0.000337

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74334

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: 0.0000942

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 1

Bravo AF: 0.0000869

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.1419T>G (p.S473R) alteration is located in exon 11 (coding exon 11) of the SRPRA gene. This alteration results from a T to G substitution at nucleotide position 1419, causing the serine (S) at amino acid position 473 to be replaced by an arginine (R). 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	0.50
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.83	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.90	N;N
REVEL	Benign	0.085
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.073	T;T
Polyphen		0.0010	B;.
Vest4		0.23
MutPred		0.45		Loss of sheet (P = 0.0054);.;
MVP		0.043
MPC		0.44
ClinPred		0.079	T
GERP RS		0.47
Varity_R		0.69
gMVP		0.58

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

Other links and lift over

dbSNP: rs199983442; hg19: chr11-126134960;