15-99105549-A-T

Variant names:

• chr15-99105549-A-T
• rs1473119271
• NM_145728.3:c.350A>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.350A>T​(p.Gln117Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000828 in 1,207,526 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q117H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: SYNM NM_145728.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.709
• 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=0.21831074).
• BS2: High AC in GnomAdExome4 at 8 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.350A>T	p.Gln117Leu	missense	Exon 1 of 4	NP_663780.2	O15061-1
	SYNM	NM_015286.6		c.350A>T	p.Gln117Leu	missense	Exon 1 of 5	NP_056101.5
	SYNM-AS1	NR_187219.1		n.190+139T>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.350A>T	p.Gln117Leu	missense	Exon 1 of 4	ENSP00000336775.7	O15061-1
	SYNM	ENST00000594047.2	TSL:1	c.350A>T	p.Gln117Leu	missense	Exon 1 of 5	ENSP00000472953.1	O15061-2
	SYNM	ENST00000328642.11	TSL:1	c.350A>T	p.Gln117Leu	missense	Exon 1 of 4	ENSP00000330469.8	O15061-3

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000666

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000756 AC: 8 AN: 1058480 Hom.: 0 Cov.: 29 AF XY: 0.00000594 AC XY: 3 AN XY: 504926

African (AFR) AF: 0.00 AC: 0 AN: 21210

American (AMR) AF: 0.000690 AC: 5 AN: 7244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12358

East Asian (EAS) AF: 0.00 AC: 0 AN: 21966

South Asian (SAS) AF: 0.00 AC: 0 AN: 23642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2736

European-Non Finnish (NFE) AF: 0.00000220 AC: 2 AN: 908164

Other (OTH) AF: 0.0000244 AC: 1 AN: 40942

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149046 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72646

African (AFR) AF: 0.0000244 AC: 1 AN: 41052

American (AMR) AF: 0.0000666 AC: 1 AN: 15020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66820

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.00 Hom.: 0

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	0.15
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.59	T
PhyloP100		-0.71
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.28
Sift	Benign	0.046	D
Sift4G	Uncertain	0.030	D
Polyphen		0.0	B
Vest4		0.25
MutPred		0.54		Gain of stability (P = 0.0076)
MVP		0.43
MPC		0.15
ClinPred		0.055	T
GERP RS		-1.1
PromoterAI		0.090	Neutral
gMVP		0.45
Mutation Taster		=75/25	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: rs1473119271; hg19: chr15-99645755;