rs3764482

Variant names:

• chr18-48942576-G-A
• rs3764482
• NM_005904.4:c.668-21C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001190823.2(SMAD7):​c.83C>T​(p.Ser28Phe) variant causes a missense 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. 5/5 in silico tools predict 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_001190823.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.11

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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	c.668-21C>T		intron_variant	Intron 2 of 3	ENST00000262158.8	NP_005895.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20487 AN: 152150 Hom.: 1706 Cov.: 32

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

GnomAD3 exomes AF: 0.143 AC: 35737 AN: 249634 Hom.: 3095 AF XY: 0.145 AC XY: 19627 AN XY: 135138

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 SAS exome AF: 0.0781

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.: 31 AF XY: 0.172 AC XY: 124785 AN XY: 726312

Gnomad4 AFR exome AF: 0.0355

Gnomad4 AMR exome AF: 0.0981

Gnomad4 ASJ exome AF: 0.231

Gnomad4 EAS exome AF: 0.0477

Gnomad4 SAS exome AF: 0.0823

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.190

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.135 AC: 20484 AN: 152268 Hom.: 1706 Cov.: 32 AF XY: 0.133 AC XY: 9887 AN XY: 74434

Gnomad4 AFR AF: 0.0414

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.232

Gnomad4 EAS AF: 0.0650

Gnomad4 SAS AF: 0.0795

Gnomad4 FIN AF: 0.184

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.148

Alfa AF: 0.182 Hom.: 2610

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

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	15
DANN	Benign	0.78

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

LitVar

Other links and lift over

dbSNP: rs3764482; hg19: chr18-46468946; COSMIC: COSV50991228;