19-43612519-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001145641.2(SRRM5):ā€‹c.398A>Gā€‹(p.Lys133Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,551,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000011 ( 0 hom. )

Consequence

SRRM5
NM_001145641.2 missense

Scores

1
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.569
Variant links:
Genes affected
SRRM5 (HGNC:37248): (serine/arginine repetitive matrix 5)
ZNF428 (HGNC:20804): (zinc finger protein 428) Predicted to enable metal ion binding activity. [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 -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.045333177).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SRRM5NM_001145641.2 linkuse as main transcriptc.398A>G p.Lys133Arg missense_variant 1/1 ENST00000417606.3
ZNF428NM_182498.4 linkuse as main transcriptc.76+1710T>C intron_variant ENST00000300811.8
ZNF428XM_047438168.1 linkuse as main transcriptc.76+1710T>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SRRM5ENST00000417606.3 linkuse as main transcriptc.398A>G p.Lys133Arg missense_variant 1/1 NM_001145641.2 P1
ZNF428ENST00000300811.8 linkuse as main transcriptc.76+1710T>C intron_variant 1 NM_182498.4 P1
SRRM5ENST00000607544.1 linkuse as main transcriptc.398A>G p.Lys133Arg missense_variant 3/32 P1
ZNF428ENST00000598676.1 linkuse as main transcriptc.76+1710T>C intron_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152054
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:
0.000386
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000130
AC:
2
AN:
154010
Hom.:
0
AF XY:
0.0000245
AC XY:
2
AN XY:
81720
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000184
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000114
AC:
16
AN:
1399234
Hom.:
0
Cov.:
30
AF XY:
0.00000724
AC XY:
5
AN XY:
690136
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000448
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152054
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74272
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 19, 2023The c.398A>G (p.K133R) alteration is located in exon 1 (coding exon 1) of the SRRM5 gene. This alteration results from a A to G substitution at nucleotide position 398, causing the lysine (K) at amino acid position 133 to be replaced by an arginine (R). 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
Benign
0.093
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0037
T;T
Eigen
Benign
-0.61
Eigen_PC
Benign
-0.52
FATHMM_MKL
Benign
0.61
D
M_CAP
Benign
0.0082
T
MetaRNN
Benign
0.045
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.55
N;N
MutationTaster
Benign
1.0
D;N;N
PrimateAI
Benign
0.35
T
Sift4G
Benign
0.26
T;T
Polyphen
0.041
B;B
Vest4
0.12
MutPred
0.27
Loss of methylation at K133 (P = 0.0332);Loss of methylation at K133 (P = 0.0332);
MVP
0.014
MPC
0.015
ClinPred
0.27
T
GERP RS
1.0
Varity_R
0.11
gMVP
0.016

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs200156648; hg19: chr19-44116671; API