Genetic Variant SMTN:c.-80-191C>G (chr22-31082988-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001382642.1(SMTN):c.188C>G(p.Pro63Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000557 in 1,437,002 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000039 ( 1 hom. )

Consequence

SMTN
NM_001382642.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.685

Publications

0 publications found

Variant links:

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 links:

ENSG00000273387 (HGNC:):

ENSG00000273387 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06398803).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382642.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMTN	NM_134269.3	MANE Select	c.-80-191C>G		intron	N/A	NP_599031.1	P53814-5
SMTN	NM_001382642.1		c.188C>G	p.Pro63Arg	missense	Exon 3 of 23	NP_001369571.1
SMTN	NM_001207017.1		c.68C>G	p.Pro23Arg	missense	Exon 1 of 21	NP_001193946.1	A0A087X1R1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMTN	ENST00000333137.12	TSL:1 MANE Select	c.-80-191C>G		intron	N/A	ENSP00000329532.7	P53814-5
SMTN	ENST00000347557.6	TSL:1	c.-80-191C>G		intron	N/A	ENSP00000328635.5	P53814-1
SMTN	ENST00000619644.5	TSL:2	c.68C>G	p.Pro23Arg	missense	Exon 1 of 21	ENSP00000484398.1	A0A087X1R1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000389

AC:

AN:

1284794

Hom.:

Cov.:

AF XY:

0.00000626

AC XY:

AN XY:

639038

show subpopulations

African (AFR)

AF:

0.0000341

AC:

AN:

29358

American (AMR)

AF:

0.00

AC:

AN:

35572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24458

East Asian (EAS)

AF:

0.00

AC:

AN:

35188

South Asian (SAS)

AF:

0.00

AC:

AN:

76960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5470

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

975428

Other (OTH)

AF:

0.0000737

AC:

AN:

54242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.61

(source)

DANN

Benign

0.64

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.47

MetaRNN

Benign

0.064

MetaSVM

Benign

-1.0

PhyloP100

-0.69

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.7

REVEL

Benign

0.017

Sift

Pathogenic

0.0

Sift4G

Benign

0.17

Vest4

0.081

MutPred

0.21

Gain of sheet (P = 0.0827)

MVP

0.068

ClinPred

0.055

GERP RS

0.73

PromoterAI

0.036

Neutral

(source)

gMVP

0.062

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over