NM_134269.3:c.85C>T

Variant names:

• chr22-31087998-C-T
• rs776743466
• NM_134269.3:c.85C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_134269.3(SMTN):​c.85C>T​(p.Arg29Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,455,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R29H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SMTN NM_134269.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23
• Publications: 1 publications found

Genes affected

SMTN (HGNC:11126): (smoothelin) This gene encodes a structural protein that is found exclusively in contractile smooth muscle cells. It associates with stress fibers and constitutes part of the cytoskeleton. This gene is localized to chromosome 22q12.3, distal to the TUPLE1 locus and outside the DiGeorge syndrome deletion. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25135952).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_134269.3. 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
	SMTN	NM_134269.3	MANE Select	c.85C>T	p.Arg29Cys	missense	Exon 3 of 21	NP_599031.1	P53814-5
	SMTN	NM_001382642.1		c.367C>T	p.Arg123Cys	missense	Exon 5 of 23	NP_001369571.1
	SMTN	NM_001207017.1		c.247C>T	p.Arg83Cys	missense	Exon 3 of 21	NP_001193946.1	A0A087X1R1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMTN	ENST00000333137.12	TSL:1 MANE Select	c.85C>T	p.Arg29Cys	missense	Exon 3 of 21	ENSP00000329532.7	P53814-5
	SMTN	ENST00000347557.6	TSL:1	c.85C>T	p.Arg29Cys	missense	Exon 3 of 20	ENSP00000328635.5	P53814-1
	SMTN	ENST00000619644.5	TSL:2	c.247C>T	p.Arg83Cys	missense	Exon 3 of 21	ENSP00000484398.1	A0A087X1R1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000813 AC: 2 AN: 246056 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1455100 Hom.: 0 Cov.: 31 AF XY: 0.00000415 AC XY: 3 AN XY: 722756

African (AFR) AF: 0.0000300 AC: 1 AN: 33358

American (AMR) AF: 0.0000225 AC: 1 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 86032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107408

Other (OTH) AF: 0.00 AC: 0 AN: 59994

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	-0.31
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.078	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.21		Loss of MoRF binding (P = 0.0626)
MVP		0.26
MPC		0.57
ClinPred		0.95	D
GERP RS		2.5
PromoterAI		-0.082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.36
Mutation Taster		=94/6	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: rs776743466; hg19: chr22-31483984; COSMIC: COSV100294793; COSMIC: COSV100294793;