chr15-99105335-C-T

Variant names:

• chr15-99105335-C-T
• rs201246890
• NM_145728.3:c.136C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_145728.3(SYNM):​c.136C>T​(p.Arg46Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000474 in 1,540,014 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: SYNM NM_145728.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20009434).
• BS2: High AC in GnomAd4 at 41 AD gene.

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.136C>T	p.Arg46Trp	missense	Exon 1 of 4	NP_663780.2	O15061-1
	SYNM	NM_015286.6		c.136C>T	p.Arg46Trp	missense	Exon 1 of 5	NP_056101.5
	SYNM-AS1	NR_187219.1		n.190+353G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNM	ENST00000336292.11	TSL:1 MANE Select	c.136C>T	p.Arg46Trp	missense	Exon 1 of 4	ENSP00000336775.7	O15061-1
	SYNM	ENST00000594047.2	TSL:1	c.136C>T	p.Arg46Trp	missense	Exon 1 of 5	ENSP00000472953.1	O15061-2
	SYNM	ENST00000328642.11	TSL:1	c.136C>T	p.Arg46Trp	missense	Exon 1 of 4	ENSP00000330469.8	O15061-3

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 151908 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000296 AC: 41 AN: 138520 AF XY: 0.000252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000734

Gnomad OTH exome AF: 0.000240

GnomAD4 exome AF: 0.000496 AC: 689 AN: 1388106 Hom.: 1 Cov.: 30 AF XY: 0.000428 AC XY: 293 AN XY: 685094

African (AFR) AF: 0.00 AC: 0 AN: 31060

American (AMR) AF: 0.00 AC: 0 AN: 35638

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25084

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35654

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 79044

European-Finnish (FIN) AF: 0.0000724 AC: 3 AN: 41422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4896

European-Non Finnish (NFE) AF: 0.000627 AC: 676 AN: 1077610

Other (OTH) AF: 0.000121 AC: 7 AN: 57698

GnomAD4 genome AF: 0.000270 AC: 41 AN: 151908 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74204

African (AFR) AF: 0.0000242 AC: 1 AN: 41334

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000589 AC: 40 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000397 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000280 AC: 2

ExAC AF: 0.000125 AC: 10

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.33	T
PhyloP100		3.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.49
Sift	Benign	0.057	T
Sift4G	Uncertain	0.015	D
Polyphen		0.42	B
Vest4		0.37
MVP		0.75
MPC		0.67
ClinPred		0.15	T
GERP RS		3.1
PromoterAI		-0.058	Neutral
gMVP		0.46
Mutation Taster		=87/13	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: rs201246890; hg19: chr15-99645541;