NM_145728.3:c.344C>G

Variant names:

• chr15-99105543-C-G
• rs782647218
• NM_145728.3:c.344C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145728.3(SYNM):​c.344C>G​(p.Ala115Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000939 in 1,065,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A115V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.4e-7 (0 hom.)
• Consequence: SYNM NM_145728.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.524
• 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-AS1 (HGNC:55421): (SYNM antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32023066).

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.344C>G	p.Ala115Gly	missense	Exon 1 of 4	NP_663780.2	O15061-1
	SYNM	NM_015286.6		c.344C>G	p.Ala115Gly	missense	Exon 1 of 5	NP_056101.5
	SYNM-AS1	NR_187219.1		n.190+145G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNM	ENST00000336292.11	TSL:1 MANE Select	c.344C>G	p.Ala115Gly	missense	Exon 1 of 4	ENSP00000336775.7	O15061-1
	SYNM	ENST00000594047.2	TSL:1	c.344C>G	p.Ala115Gly	missense	Exon 1 of 5	ENSP00000472953.1	O15061-2
	SYNM	ENST00000328642.11	TSL:1	c.344C>G	p.Ala115Gly	missense	Exon 1 of 4	ENSP00000330469.8	O15061-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.39e-7 AC: 1 AN: 1065342 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 508916

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21366

American (AMR) AF: 0.00 AC: 0 AN: 7432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12622

East Asian (EAS) AF: 0.00 AC: 0 AN: 22322

South Asian (SAS) AF: 0.00 AC: 0 AN: 24718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2760

European-Non Finnish (NFE) AF: 0.00000110 AC: 1 AN: 912220

Other (OTH) AF: 0.00 AC: 0 AN: 41316

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.33	T
PhyloP100		-0.52
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.26
Sift	Benign	0.38	T
Sift4G	Benign	0.28	T
Polyphen		0.95	P
Vest4		0.21
MutPred		0.38		Loss of MoRF binding (P = 0.1342)
MVP		0.85
MPC		0.57
ClinPred		0.86	D
GERP RS		3.6
PromoterAI		-0.024	Neutral
gMVP		0.35
Mutation Taster		=90/10	polymorphism

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

dbSNP: rs782647218; hg19: chr15-99645749;