15-99129394-C-T

Variant names:

• chr15-99129394-C-T
• NM_145728.3:c.1034C>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.562

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)

ACMG classification

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
SYNM	NM_145728.3	c.1034C>T	p.Thr345Ile	missense_variant	Exon 4 of 4	ENST00000336292.11	NP_663780.2
SYNM	NM_015286.6	c.1034C>T	p.Thr345Ile	missense_variant	Exon 4 of 5		NP_056101.5
SYNM	XM_017022035.2	c.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
SYNM	ENST00000336292.11	c.1034C>T	p.Thr345Ile	missense_variant	Exon 4 of 4	1	NM_145728.3	ENSP00000336775.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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;