15-99130143-G-T

Variant names:

• chr15-99130143-G-T
• NM_145728.3:c.1783G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145728.3(SYNM):​c.1783G>T​(p.Gly595Cys) 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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNM NM_145728.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.682

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15870255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNM	NM_145728.3	c.1783G>T	p.Gly595Cys	missense_variant	Exon 4 of 4	ENST00000336292.11	NP_663780.2
SYNM	NM_015286.6	c.1783G>T	p.Gly595Cys	missense_variant	Exon 4 of 5		NP_056101.5
SYNM	XM_017022035.2	c.1783G>T	p.Gly595Cys	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.1783G>T	p.Gly595Cys	missense_variant	Exon 4 of 4	1	NM_145728.3	ENSP00000336775.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1783G>T (p.G595C) alteration is located in exon 4 (coding exon 4) of the SYNM gene. This alteration results from a G to T substitution at nucleotide position 1783, causing the glycine (G) at amino acid position 595 to be replaced by a cysteine (C). 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	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	.;.;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.70	T;.;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	N;.;.
REVEL	Benign	0.084
Sift	Benign	0.043	D;.;.
Sift4G	Uncertain	0.045	D;T;T
Vest4		0.30
MutPred		0.28		.;Gain of methylation at K594 (P = 0.019);Gain of methylation at K594 (P = 0.019);
MVP		0.48
MPC		0.60
ClinPred		0.36	T
GERP RS		1.7
gMVP		0.36

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: chr15-99670348;