NM_134269.3:c.136G>T

Variant names:

• chr22-31088049-G-T
• rs142234684
• NM_134269.3:c.136G>T

Variant summary

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

The NM_134269.3(SMTN):​c.136G>T​(p.Glu46*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000363 in 1,459,894 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: SMTN NM_134269.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.23
• Publications: 2 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.136G>T	p.Glu46*	stop_gained	Exon 3 of 21	NP_599031.1	P53814-5
	SMTN	NM_001382642.1		c.418G>T	p.Glu140*	stop_gained	Exon 5 of 23	NP_001369571.1
	SMTN	NM_001207017.1		c.298G>T	p.Glu100*	stop_gained	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.136G>T	p.Glu46*	stop_gained	Exon 3 of 21	ENSP00000329532.7	P53814-5
	SMTN	ENST00000347557.6	TSL:1	c.136G>T	p.Glu46*	stop_gained	Exon 3 of 20	ENSP00000328635.5	P53814-1
	SMTN	ENST00000619644.5	TSL:2	c.298G>T	p.Glu100*	stop_gained	Exon 3 of 21	ENSP00000484398.1	A0A087X1R1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1459894 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 726016

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1110910

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.2
Vest4		0.73
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		-0.073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=7/193	disease causing (fs/PTC)

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: rs142234684; hg19: chr22-31484035;