rs3205187

Variant names:

• chr22-31095309-G-C
• rs3205187
• NM_134269.3:c.1639G>C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 35 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
SMTN	NM_134269.3	c.1639G>C	p.Ala547Pro	missense_variant	Exon 12 of 21	ENST00000333137.12	NP_599031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMTN	ENST00000333137.12	c.1639G>C	p.Ala547Pro	missense_variant	Exon 12 of 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

GnomAD2 exomes AF: 0.573 AC: 143797 AN: 250912 AF XY: 0.585

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 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

African (AFR) AF: 0.495 AC: 16554 AN: 33454

American (AMR) AF: 0.484 AC: 21611 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 17313 AN: 26130

East Asian (EAS) AF: 0.109 AC: 4329 AN: 39700

South Asian (SAS) AF: 0.623 AC: 53666 AN: 86210

European-Finnish (FIN) AF: 0.575 AC: 30693 AN: 53366

Middle Eastern (MID) AF: 0.704 AC: 3816 AN: 5422

European-Non Finnish (NFE) AF: 0.661 AC: 735261 AN: 1111718

Other (OTH) AF: 0.615 AC: 37130 AN: 60344

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

African (AFR) AF: 0.501 AC: 20780 AN: 41494

American (AMR) AF: 0.541 AC: 8267 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2274 AN: 3472

East Asian (EAS) AF: 0.124 AC: 640 AN: 5182

South Asian (SAS) AF: 0.621 AC: 2992 AN: 4820

European-Finnish (FIN) AF: 0.568 AC: 6013 AN: 10592

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44788 AN: 67990

Other (OTH) AF: 0.618 AC: 1307 AN: 2116

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;.;.;.;.
PhyloP100		1.5
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
PromoterAI		-0.014	Neutral
Varity_R		0.055
gMVP		0.26
Mutation Taster		=100/0	polymorphism (auto)

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