1-24651410-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_005839.4(SRRM1):​c.523C>T​(p.Arg175Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000682 in 1,613,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

SRRM1
NM_005839.4 missense, splice_region

Scores

4
5
10
Splicing: ADA: 0.9824
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.66
Variant links:
Genes affected
SRRM1 (HGNC:16638): (serine and arginine repetitive matrix 1) Enables RNA binding activity. Predicted to be involved in mRNA splicing, via spliceosome. Located in nuclear speck. Part of catalytic step 2 spliceosome. Biomarker of gestational diabetes. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
BS2
High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SRRM1NM_005839.4 linkc.523C>T p.Arg175Cys missense_variant, splice_region_variant Exon 6 of 17 ENST00000323848.14 NP_005830.2 Q8IYB3-1A0A0S2Z4W1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SRRM1ENST00000323848.14 linkc.523C>T p.Arg175Cys missense_variant, splice_region_variant Exon 6 of 17 1 NM_005839.4 ENSP00000326261.8 Q8IYB3-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000116
AC:
29
AN:
249522
Hom.:
0
AF XY:
0.000111
AC XY:
15
AN XY:
135040
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00210
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000712
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000678
AC:
99
AN:
1460838
Hom.:
0
Cov.:
30
AF XY:
0.0000743
AC XY:
54
AN XY:
726744
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00142
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000477
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000165
Hom.:
0
Bravo
AF:
0.0000680
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Mar 02, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.523C>T (p.R175C) alteration is located in exon 6 (coding exon 6) of the SRRM1 gene. This alteration results from a C to T substitution at nucleotide position 523, causing the arginine (R) at amino acid position 175 to be replaced by a cysteine (C). 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
Pathogenic
0.85
BayesDel_addAF
Benign
-0.077
T
BayesDel_noAF
Benign
-0.17
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Benign
0.068
T;T;.;T
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.82
T;T;T;T
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.064
T;T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Uncertain
2.0
M;.;.;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-2.5
N;D;N;.
REVEL
Benign
0.24
Sift
Pathogenic
0.0
.;D;D;.
Sift4G
Benign
0.15
T;T;T;D
Polyphen
0.40
B;.;P;.
Vest4
0.49
MVP
0.25
MPC
0.50
ClinPred
0.22
T
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.23
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Pathogenic
0.79
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: rs200425080; hg19: chr1-24977901; API