NM_145728.3:c.1034C>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -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 VariationId is 3058385.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145728.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNM	NM_145728.3	MANE Select	c.1034C>T	p.Thr345Ile	missense	Exon 4 of 4	NP_663780.2	O15061-1
	SYNM	NM_015286.6		c.1034C>T	p.Thr345Ile	missense	Exon 4 of 5	NP_056101.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNM	ENST00000336292.11	TSL:1 MANE Select	c.1034C>T	p.Thr345Ile	missense	Exon 4 of 4	ENSP00000336775.7	O15061-1
	SYNM	ENST00000594047.2	TSL:1	c.1034C>T	p.Thr345Ile	missense	Exon 4 of 5	ENSP00000472953.1	O15061-2
	SYNM	ENST00000560674.5	TSL:1	c.176C>T	p.Thr59Ile	missense	Exon 4 of 5	ENSP00000453040.1	H0YL34

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	-	1	SYNM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.40	T
PhyloP100		-0.56
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Vest4		0.16
MutPred		0.65		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

Other links and lift over

hg19: chr15-99669599;