15-99129394-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_145728.3(SYNM):​c.1034C>T​(p.Thr345Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

SYNM
NM_145728.3 missense

Scores

7
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.562
Variant links:
Genes affected
SYNM (HGNC:24466): (synemin) The protein encoded by this gene is an intermediate filament (IF) family member. IF proteins are cytoskeletal proteins that confer resistance to mechanical stress and are encoded by a dispersed multigene family. This protein has been found to form a linkage between desmin, which is a subunit of the IF network, and the extracellular matrix, and provides an important structural support in muscle. Two alternatively spliced variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]
SYNM-AS2 (HGNC:56228): (SYNM antisense RNA 2)

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2170743).
BP6
Variant 15-99129394-C-T is Benign according to our data. Variant chr15-99129394-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3058385.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYNMNM_145728.3 linkc.1034C>T p.Thr345Ile missense_variant Exon 4 of 4 ENST00000336292.11 NP_663780.2 O15061-1
SYNMNM_015286.6 linkc.1034C>T p.Thr345Ile missense_variant Exon 4 of 5 NP_056101.5 O15061-2A0A075B7B1
SYNMXM_017022035.2 linkc.1034C>T p.Thr345Ile missense_variant Exon 4 of 5 XP_016877524.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYNMENST00000336292.11 linkc.1034C>T p.Thr345Ile missense_variant Exon 4 of 4 1 NM_145728.3 ENSP00000336775.7 O15061-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1034C>T (p.T345I) alteration is located in exon 4 (coding exon 4) of the SYNM gene. This alteration results from a C to T substitution at nucleotide position 1034, causing the threonine (T) at amino acid position 345 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SYNM-related disorder Benign:1
Mar 07, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Uncertain
0.019
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
8.7
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
.;.;T
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.58
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.71
T;.;T
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.22
T;T;T
MetaSVM
Benign
-0.40
T
PrimateAI
Benign
0.32
T
PROVEAN
Uncertain
-2.6
D;.;.
REVEL
Uncertain
0.45
Sift
Uncertain
0.0030
D;.;.
Sift4G
Uncertain
0.0050
D;D;D
Vest4
0.16
MutPred
0.65
.;Gain of catalytic residue at T345 (P = 0.0054);Gain of catalytic residue at T345 (P = 0.0054);
MVP
0.71
MPC
0.29
ClinPred
0.43
T
GERP RS
2.4
gMVP
0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-99669599; API