19-43612324-C-T

Variant summary

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

The NM_001145641.2(SRRM5):​c.203C>T​(p.Thr68Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000516 in 1,551,562 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 (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SRRM5
NM_001145641.2 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.589
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=0.06501722).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SRRM5NM_001145641.2 linkc.203C>T p.Thr68Ile missense_variant Exon 1 of 1 ENST00000417606.3 NP_001139113.1 B3KS81Q4G0Z0
ZNF428NM_182498.4 linkc.76+1905G>A intron_variant Intron 2 of 2 ENST00000300811.8 NP_872304.2 Q96B54I6L9C8
ZNF428XM_047438168.1 linkc.76+1905G>A intron_variant Intron 3 of 3 XP_047294124.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SRRM5ENST00000417606.3 linkc.203C>T p.Thr68Ile missense_variant Exon 1 of 1 6 NM_001145641.2 ENSP00000414512.1 B3KS81
ZNF428ENST00000300811.8 linkc.76+1905G>A intron_variant Intron 2 of 2 1 NM_182498.4 ENSP00000300811.2 Q96B54
SRRM5ENST00000607544.1 linkc.203C>T p.Thr68Ile missense_variant Exon 3 of 3 2 ENSP00000476253.1 B3KS81
ZNF428ENST00000598676.1 linkc.76+1905G>A intron_variant Intron 2 of 3 5 ENSP00000469484.1 M0QXZ5

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000143
AC:
2
AN:
1399426
Hom.:
0
Cov.:
30
AF XY:
0.00000145
AC XY:
1
AN XY:
690226
show subpopulations
Gnomad4 AFR exome
AF:
0.0000316
Gnomad4 AMR exome
AF:
0.0000280
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.000145
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000982

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.203C>T (p.T68I) alteration is located in exon 1 (coding exon 1) of the SRRM5 gene. This alteration results from a C to T substitution at nucleotide position 203, causing the threonine (T) at amino acid position 68 to be replaced by an isoleucine (I). 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
0.22
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
14
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0029
T;T
Eigen
Benign
-0.89
Eigen_PC
Benign
-0.96
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.39
.;T
M_CAP
Benign
0.0045
T
MetaRNN
Benign
0.065
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
N;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-1.0
.;N
REVEL
Benign
0.039
Sift
Benign
0.26
.;T
Sift4G
Benign
0.53
T;T
Polyphen
0.43
B;B
Vest4
0.060
MVP
0.014
MPC
0.018
ClinPred
0.20
T
GERP RS
0.39
Varity_R
0.064
gMVP
0.021

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: rs867398191; hg19: chr19-44116476; API