dbSNP rs3764482: SMAD7:c.668-21C>T (chr18-48942576-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_005904.4(SMAD7):c.668-21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,612,284 control chromosomes in the GnomAD database, including 25,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.13 ( 1706 hom., cov: 32)

Exomes 𝑓: 0.17 ( 23417 hom. )

Consequence

SMAD7
NM_005904.4 intron

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.11

Publications

33 publications found

Variant links:

Genes affected

SMAD7 (HGNC:6773): (SMAD family member 7) The protein encoded by this gene is a nuclear protein that binds the E3 ubiquitin ligase SMURF2. Upon binding, this complex translocates to the cytoplasm, where it interacts with TGF-beta receptor type-1 (TGFBR1), leading to the degradation of both the encoded protein and TGFBR1. Expression of this gene is induced by TGFBR1. Variations in this gene are a cause of susceptibility to colorectal cancer type 3 (CRCS3). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

SMAD7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 18-48942576-G-A is Benign according to our data. Variant chr18-48942576-G-A is described in ClinVar as Benign. ClinVar VariationId is 3059472.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD7	NM_005904.4 link	c.668-21C>T		intron_variant	Intron 2 of 3	ENST00000262158.8	NP_005895.1	O15105-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD7	ENST00000262158.8 link	c.668-21C>T		intron_variant	Intron 2 of 3	1	NM_005904.4	ENSP00000262158.2		O15105-1

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

20487

AN:

152150

Hom.:

1706

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0414

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.125

Gnomad ASJ

AF:

0.232

Gnomad EAS

AF:

0.0660

Gnomad SAS

AF:

0.0786

Gnomad FIN

AF:

0.184

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.190

Gnomad OTH

AF:

0.150

GnomAD2 exomes

AF:

0.143

AC:

35737

AN:

249634

AF XY:

0.145

show subpopulations

Gnomad AFR exome

AF:

0.0379

Gnomad AMR exome

AF:

0.0928

Gnomad ASJ exome

AF:

0.231

Gnomad EAS exome

AF:

0.0602

Gnomad FIN exome

AF:

0.178

Gnomad NFE exome

AF:

0.188

Gnomad OTH exome

AF:

0.174

GnomAD4 exome

AF:

0.173

AC:

252653

AN:

1460016

Hom.:

23417

Cov.:

AF XY:

0.172

AC XY:

124785

AN XY:

726312

show subpopulations

African (AFR)

AF:

0.0355

AC:

1186

AN:

33450

American (AMR)

AF:

0.0981

AC:

4367

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

6030

AN:

26086

East Asian (EAS)

AF:

0.0477

AC:

1891

AN:

39646

South Asian (SAS)

AF:

0.0823

AC:

7082

AN:

86068

European-Finnish (FIN)

AF:

0.179

AC:

9538

AN:

53172

Middle Eastern (MID)

AF:

0.210

AC:

1208

AN:

5766

European-Non Finnish (NFE)

AF:

0.190

AC:

211193

AN:

1111014

Other (OTH)

AF:

0.168

AC:

10158

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

9986

19971

29957

39942

49928

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7238

14476

21714

28952

36190

<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:

0.135

AC:

20484

AN:

152268

Hom.:

1706

Cov.:

AF XY:

0.133

AC XY:

9887

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0414

AC:

1721

AN:

41562

American (AMR)

AF:

0.124

AC:

1904

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

807

AN:

3472

East Asian (EAS)

AF:

0.0650

AC:

337

AN:

5182

South Asian (SAS)

AF:

0.0795

AC:

384

AN:

4830

European-Finnish (FIN)

AF:

0.184

AC:

1947

AN:

10584

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.190

AC:

12923

AN:

68018

Other (OTH)

AF:

0.148

AC:

313

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

896

1793

2689

3586

4482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

224

448

672

896

1120

<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:

0.171

Hom.:

4355

Bravo

AF:

0.129

Asia WGS

AF:

0.0780

AC:

272

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

SMAD7-related disorder

Benign:1

Nov 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over