11-126265036-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003139.4(SRPRA):c.1448G>A(p.Gly483Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0098 in 1,614,186 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (5 hom., cov: 33)
  • Exomes 𝑓: 0.010 (93 hom.)
• Consequence: SRPRA NM_003139.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.54

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010002643).
• BP6: Variant 11-126265036-C-T is Benign according to our data. Variant chr11-126265036-C-T is described in ClinVar as [Benign]. Clinvar id is 2642522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 915 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRPRA	NM_003139.4	c.1448G>A	p.Gly483Asp	missense_variant	11/14	ENST00000332118.11
SRPRA	NM_001177842.2	c.1364G>A	p.Gly455Asp	missense_variant	10/13
SRPRA	XM_047427497.1	c.1448G>A	p.Gly483Asp	missense_variant	11/14
SRPRA	XM_017018179.3	c.1448G>A	p.Gly483Asp	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRPRA	ENST00000332118.11	c.1448G>A	p.Gly483Asp	missense_variant	11/14	1	NM_003139.4	P1
SRPRA	ENST00000532259.1	c.1364G>A	p.Gly455Asp	missense_variant	10/13	2
SRPRA	ENST00000531104.1	n.527G>A		non_coding_transcript_exon_variant	2/2	2
SRPRA	ENST00000527817.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 915 AN: 152208 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00528 AC: 1327 AN: 251404 Hom.: 9 AF XY: 0.00530 AC XY: 720 AN XY: 135870

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.00982

Gnomad OTH exome AF: 0.00537

GnomAD4 exome AF: 0.0102 AC: 14904 AN: 1461860 Hom.: 93 Cov.: 32 AF XY: 0.00991 AC XY: 7206 AN XY: 727226

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00491

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.00848

GnomAD4 genome AF: 0.00601 AC: 915 AN: 152326 Hom.: 5 Cov.: 33 AF XY: 0.00503 AC XY: 375 AN XY: 74486

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00938 Hom.: 8

Bravo AF: 0.00574

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.0122 AC: 105

ExAC AF: 0.00504 AC: 612

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00949

EpiControl AF: 0.00925

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

SRPRA: BS1, BS2 -

SRPRA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.37
Sift	Benign	0.047	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.38	B;.
Vest4		0.83
MVP		0.64
MPC		1.4
ClinPred		0.033	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs114538197; hg19: chr11-126134931; COSMIC: COSV99703242; COSMIC: COSV99703242;