rs3764482

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S28C) has been classified as Uncertain significance.

• 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
• Publications: 33 publications found

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 Gene-Disease associations (from GenCC):

• colorectal cancer, susceptibility to, 3

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190823.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD7	NM_005904.4	MANE Select	c.668-21C>T		intron	N/A	NP_005895.1	O15105-1
	SMAD7	NM_001190823.2		c.83C>T	p.Ser28Phe	missense	Exon 1 of 2	NP_001177752.1	B3KYA8
	SMAD7	NM_001190821.2		c.668-24C>T		intron	N/A	NP_001177750.1	O15105-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD7	ENST00000262158.8	TSL:1 MANE Select	c.668-21C>T		intron	N/A	ENSP00000262158.2	O15105-1
	SMAD7	ENST00000589634.1	TSL:4	c.668-24C>T		intron	N/A	ENSP00000467621.1	O15105-3
	SMAD7	ENST00000911789.1		c.667+5808C>T		intron	N/A	ENSP00000581848.1

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

GnomAD2 exomes AF: 0.143 AC: 35737 AN: 249634 AF XY: 0.145

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

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

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

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: 48 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12923 AN: 68018

Other (OTH) AF: 0.148 AC: 313 AN: 2114

Alfa AF: 0.171 Hom.: 4355

Bravo AF: 0.129

Asia WGS AF: 0.0780 AC: 272 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SMAD7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.78
PhyloP100		1.1
Mutation Taster		=100/0	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: rs3764482; hg19: chr18-46468946; COSMIC: COSV50991228;