11-126265173-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_003139.4(SRPRA):​c.1312-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SRPRA
NM_003139.4 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.92
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11163276 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7, offset of -27, new splice context is: tctcaaaatcctggctttAGgtg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SRPRANM_003139.4 linkc.1312-1G>A splice_acceptor_variant, intron_variant Intron 10 of 13 ENST00000332118.11 NP_003130.2 P08240-1
SRPRANM_001177842.2 linkc.1228-1G>A splice_acceptor_variant, intron_variant Intron 9 of 12 NP_001171313.1 P08240-2
SRPRAXM_047427497.1 linkc.1312-1G>A splice_acceptor_variant, intron_variant Intron 10 of 13 XP_047283453.1
SRPRAXM_017018179.3 linkc.1312-1G>A splice_acceptor_variant, intron_variant Intron 10 of 13 XP_016873668.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SRPRAENST00000332118.11 linkc.1312-1G>A splice_acceptor_variant, intron_variant Intron 10 of 13 1 NM_003139.4 ENSP00000328023.5 P08240-1
SRPRAENST00000532259.1 linkc.1228-1G>A splice_acceptor_variant, intron_variant Intron 9 of 12 2 ENSP00000435508.1 P08240-2
SRPRAENST00000527817.1 linkn.595-1G>A splice_acceptor_variant, intron_variant Intron 4 of 4 2
SRPRAENST00000531104.1 linkn.391-1G>A splice_acceptor_variant, intron_variant Intron 1 of 1 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

See cases Uncertain:1
Apr 10, 2022
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PM2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
32
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.98
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.67
Position offset: -20
DS_AL_spliceai
1.0
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-126135068; API