Genetic Variant SMTN:c.-80-224C>T (chr22-31082955-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001382642.1(SMTN):c.155C>T(p.Ala52Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000368 in 1,495,452 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A52A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

SMTN
NM_001382642.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.140

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.029118001).

BP6

Variant 22-31082955-C-T is Benign according to our data. Variant chr22-31082955-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2518519.Status of the report is criteria_provided_single_submitter, 1 stars.

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.-80-224C>T		intron	N/A	NP_599031.1	P53814-5
SMTN	NM_001382642.1		c.155C>T	p.Ala52Val	missense	Exon 3 of 23	NP_001369571.1
SMTN	NM_001207017.1		c.35C>T	p.Ala12Val	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.-80-224C>T		intron	N/A	ENSP00000329532.7	P53814-5
SMTN	ENST00000347557.6	TSL:1	c.-80-224C>T		intron	N/A	ENSP00000328635.5	P53814-1
SMTN	ENST00000619644.5	TSL:2	c.35C>T	p.Ala12Val	missense	Exon 1 of 21	ENSP00000484398.1	A0A087X1R1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000136

AC:

AN:

147108

AF XY:

0.0000252

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000357

AC:

AN:

1343290

Hom.:

Cov.:

AF XY:

0.0000451

AC XY:

AN XY:

665604

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30548

American (AMR)

AF:

0.00

AC:

AN:

35632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24826

East Asian (EAS)

AF:

0.0000282

AC:

AN:

35490

South Asian (SAS)

AF:

0.0000128

AC:

AN:

78156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5582

European-Non Finnish (NFE)

AF:

0.0000428

AC:

AN:

1028802

Other (OTH)

AF:

0.0000357

AC:

AN:

56100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0000460

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41420

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

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

0.072

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.6

(source)

DANN

Benign

0.50

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.39

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.0

PhyloP100

-0.14

PrimateAI

Benign

0.42

PROVEAN

Benign

0.32

REVEL

Benign

0.037

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.24

MutPred

0.28

Loss of disorder (P = 0.0712)

MVP

0.57

ClinPred

0.059

GERP RS

-0.17

PromoterAI

-0.045

Neutral

(source)

gMVP

0.073

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over