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GeneBe

2-233309263-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2_SupportingPP5_Moderate

The NM_000541.5(SAG):c.74C>A(p.Ser25Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152086 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S25S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000080 ( 0 hom. )

Consequence

SAG
NM_000541.5 stop_gained, splice_region

Scores

4
2
1
Splicing: ADA: 0.9672
1
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.24

Links

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. There are 24 pathogenic variants in the truncated region.
PM2
?
Very rare variant; Number of alleles below threshold, gnomad allele frequency = 0.00000658 (1/152086) while in subpopulation NFE AF= 0.0000147 (1/68030). AF 95% confidence interval is 0. There are 0 homozygotes in gnomad. There are 0 alleles in male gnomad subpopulation. Median coverage is 32. This position pass quality control queck.
PP5
?
Variant 2-233309263-C-A is Pathogenic according to our data. Variant chr2-233309263-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1452228.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SAGNM_000541.5 linkuse as main transcriptc.74C>A p.Ser25Ter stop_gained, splice_region_variant 2/16 ENST00000409110.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SAGENST00000409110.6 linkuse as main transcriptc.74C>A p.Ser25Ter stop_gained, splice_region_variant 2/165 NM_000541.5 P1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152086
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000804
AC:
2
AN:
248784
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134968
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:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000617
AC:
9
AN:
1459828
Hom.:
0
AF XY:
0.00000688
AC XY:
5
AN XY:
726340
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000720
Gnomad4 OTH exome
AF:
0.0000166
Bravo
AF:
0.00000378
ExAC
AF:
0.00000828
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 28, 2021This sequence change creates a premature translational stop signal (p.Ser25*) in the SAG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SAG are known to be pathogenic (PMID: 9452120, 15234147, 22665972). This variant is present in population databases (rs374930316, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SAG-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.60
Cadd
Pathogenic
40
Dann
Uncertain
1.0
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.92
D
MutationTaster
Benign
1.0
A
Vest4
0.53
GERP RS
4.5

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.97
dbscSNV1_RF
Benign
0.70
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs374930316; hg19: chr2-234217909; API