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GeneBe

2-233309263-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000541.5(SAG):c.74C>T(p.Ser25Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000316 in 152086 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S25S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

SAG
NM_000541.5 missense, splice_region

Scores

8
8
Splicing: ADA: 0.9894
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.24

Links

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SAGNM_000541.5 linkuse as main transcriptc.74C>T p.Ser25Leu missense_variant, 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>T p.Ser25Leu missense_variant, splice_region_variant 2/165 NM_000541.5 P1

Frequencies

GnomAD3 genomes
AF:
0.000316
AC:
48
AN:
152086
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00223
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:
0.000176
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000197
AC:
49
AN:
248784
Hom.:
0
AF XY:
0.000178
AC XY:
24
AN XY:
134968
show subpopulations
Gnomad AFR exome
AF:
0.000130
Gnomad AMR exome
AF:
0.000696
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:
0.000204
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000181
AC:
264
AN:
1459824
Hom.:
0
AF XY:
0.000178
AC XY:
129
AN XY:
726340
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.000783
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000193
Gnomad4 OTH exome
AF:
0.000182
Alfa
AF:
0.000112
Hom.:
0
Bravo
AF:
0.000291
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000265
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000828
AC:
10
EpiCase
AF:
0.000109
EpiControl
AF:
0.000297

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeNov 19, 2023This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 25 of the SAG protein (p.Ser25Leu). This variant is present in population databases (rs374930316, gnomAD 0.07%). This missense change has been observed in individual(s) with blindness (PMID: 32483926). ClinVar contains an entry for this variant (Variation ID: 972665). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.31
Cadd
Pathogenic
27
Dann
Uncertain
1.0
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.90
D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.092
T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
0.81
D
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-2.7
D;D;D
REVEL
Benign
0.098
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.023
D;D;D
Polyphen
0.99
.;D;.
Vest4
0.70
MVP
0.43
MPC
0.37
ClinPred
0.11
T
GERP RS
4.5
Varity_R
0.29
gMVP
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.76
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; COSMIC: COSV68590604; API