rs3205187

Positions:

• chr22-31095309-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_134269.3(SMTN):​c.1639G>C​(p.Ala547Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,613,198 control chromosomes in the GnomAD database, including 324,069 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.58 (26311 hom., cov: 33)
  • Exomes 𝑓: 0.63 (297758 hom.)
• Consequence: SMTN NM_134269.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49

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]

SMTN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.4141344E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMTN	NM_134269.3	c.1639G>C	p.Ala547Pro	missense_variant	12/21	ENST00000333137.12	NP_599031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMTN	ENST00000333137.12	c.1639G>C	p.Ala547Pro	missense_variant	12/21	1	NM_134269.3	ENSP00000329532.7

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87678 AN: 152040 Hom.: 26302 Cov.: 33

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.617

GnomAD3 exomes AF: 0.573 AC: 143797 AN: 250912 Hom.: 44136 AF XY: 0.585 AC XY: 79382 AN XY: 135650

Gnomad AFR exome AF: 0.498

Gnomad AMR exome AF: 0.476

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.112

Gnomad SAS exome AF: 0.621

Gnomad FIN exome AF: 0.572

Gnomad NFE exome AF: 0.664

Gnomad OTH exome AF: 0.622

GnomAD4 exome AF: 0.630 AC: 920373 AN: 1461040 Hom.: 297758 Cov.: 51 AF XY: 0.632 AC XY: 459547 AN XY: 726860

Gnomad4 AFR exome AF: 0.495

Gnomad4 AMR exome AF: 0.484

Gnomad4 ASJ exome AF: 0.663

Gnomad4 EAS exome AF: 0.109

Gnomad4 SAS exome AF: 0.623

Gnomad4 FIN exome AF: 0.575

Gnomad4 NFE exome AF: 0.661

Gnomad4 OTH exome AF: 0.615

GnomAD4 genome AF: 0.577 AC: 87737 AN: 152158 Hom.: 26311 Cov.: 33 AF XY: 0.570 AC XY: 42440 AN XY: 74392

Gnomad4 AFR AF: 0.501

Gnomad4 AMR AF: 0.541

Gnomad4 ASJ AF: 0.655

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.621

Gnomad4 FIN AF: 0.568

Gnomad4 NFE AF: 0.659

Gnomad4 OTH AF: 0.618

Alfa AF: 0.639 Hom.: 9709

Bravo AF: 0.569

TwinsUK AF: 0.663 AC: 2457

ALSPAC AF: 0.653 AC: 2515

ESP6500AA AF: 0.497 AC: 2190

ESP6500EA AF: 0.664 AC: 5707

ExAC AF: 0.581 AC: 70574

Asia WGS AF: 0.419 AC: 1460 AN: 3478

EpiCase AF: 0.677

EpiControl AF: 0.676

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.60
DEOGEN2	Benign	0.041	.;T;.;.;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.063	T;T;T;T;T;T;T
MetaRNN	Benign	0.0000074	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N;N;N;.;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	2.3	N;N;N;.;.;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T;.;.;T;T
Sift4G	Benign	0.87	T;T;T;T;T;T;T
Polyphen		0.0	.;B;B;.;.;.;B
Vest4		0.074
MPC		0.21
ClinPred		0.0031	T
GERP RS		3.9
Varity_R		0.055
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs3205187; hg19: chr22-31491295; COSMIC: COSV60778876; COSMIC: COSV60778876;