rs5997872

Variant names:

• chr22-31095346-C-T
• rs5997872
• NM_134269.3:c.1676C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_134269.3(SMTN):​c.1676C>T​(p.Ala559Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,613,820 control chromosomes in the GnomAD database, including 23,040 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 0.16 (2059 hom., cov: 33)
  • Exomes 𝑓: 0.17 (20981 hom.)
• Consequence: SMTN NM_134269.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.270
• Publications: 32 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=0.0013774931).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMTN	NM_134269.3	c.1676C>T	p.Ala559Val	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.1676C>T	p.Ala559Val	missense_variant	Exon 12 of 21	1	NM_134269.3	ENSP00000329532.7

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24237 AN: 152138 Hom.: 2060 Cov.: 33

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0977

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.0897

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.134

GnomAD2 exomes AF: 0.143 AC: 36028 AN: 251244 AF XY: 0.145

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.0701

Gnomad ASJ exome AF: 0.0824

Gnomad EAS exome AF: 0.0858

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.166 AC: 242315 AN: 1461564 Hom.: 20981 Cov.: 35 AF XY: 0.165 AC XY: 120255 AN XY: 727088

African (AFR) AF: 0.173 AC: 5804 AN: 33476

American (AMR) AF: 0.0754 AC: 3371 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0831 AC: 2173 AN: 26134

East Asian (EAS) AF: 0.0817 AC: 3243 AN: 39696

South Asian (SAS) AF: 0.141 AC: 12144 AN: 86248

European-Finnish (FIN) AF: 0.164 AC: 8749 AN: 53414

Middle Eastern (MID) AF: 0.177 AC: 1011 AN: 5724

European-Non Finnish (NFE) AF: 0.177 AC: 196236 AN: 1111782

Other (OTH) AF: 0.159 AC: 9584 AN: 60370

GnomAD4 genome AF: 0.159 AC: 24272 AN: 152256 Hom.: 2059 Cov.: 33 AF XY: 0.156 AC XY: 11579 AN XY: 74456

African (AFR) AF: 0.173 AC: 7182 AN: 41528

American (AMR) AF: 0.0976 AC: 1493 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 278 AN: 3472

East Asian (EAS) AF: 0.0899 AC: 466 AN: 5184

South Asian (SAS) AF: 0.140 AC: 675 AN: 4832

European-Finnish (FIN) AF: 0.153 AC: 1627 AN: 10610

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12141 AN: 68006

Other (OTH) AF: 0.133 AC: 281 AN: 2116

Alfa AF: 0.167 Hom.: 10806

Bravo AF: 0.156

TwinsUK AF: 0.173 AC: 640

ALSPAC AF: 0.171 AC: 659

ESP6500AA AF: 0.175 AC: 773

ESP6500EA AF: 0.168 AC: 1446

ExAC AF: 0.151 AC: 18336

Asia WGS AF: 0.142 AC: 493 AN: 3478

EpiCase AF: 0.165

EpiControl AF: 0.162

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.7
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	.;T;.;.;T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.52	T;T;T;T;T;T;T
MetaRNN	Benign	0.0014	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L;.;.;.;.
PhyloP100		-0.27
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.38	N;N;N;.;.;N;N
REVEL	Benign	0.030
Sift	Benign	0.58	T;T;T;.;.;T;T
Sift4G	Benign	0.40	T;T;T;T;T;T;T
Polyphen		0.0020, 0.0080, 0.0010	.;B;B;.;.;.;B
Vest4		0.031
MPC		0.16
ClinPred		0.00048	T
GERP RS		0.29
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.10
Mutation Taster		=99/1	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: rs5997872; hg19: chr22-31491332; COSMIC: COSV60776408; COSMIC: COSV60776408;