rs3736242

Variant names:

• chr18-48948376-C-T
• rs3736242
• NM_005904.4:c.667+8G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-48948376-C-T
• chr18-48948376-C-A
• chr18-48948376-C-G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BA1

The NM_005904.4(SMAD7):​c.667+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,569,362 control chromosomes in the GnomAD database, including 42,251 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.21 (3542 hom., cov: 32)
  • Exomes 𝑓: 0.23 (38709 hom.)
• Consequence: SMAD7 NM_005904.4 splice_region, intron
• Scores: Splicing: ADA: 0.01668
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.12
• Publications: 26 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 18-48948376-C-T is Benign according to our data. Variant chr18-48948376-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3060367.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005904.4. 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.667+8G>A		splice_region intron	N/A	NP_005895.1	O15105-1
	SMAD7	NM_001190821.2		c.667+8G>A		splice_region intron	N/A	NP_001177750.1	O15105-3
	SMAD7	NM_001190822.2		c.22+8G>A		splice_region intron	N/A	NP_001177751.1	O15105-2

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32373 AN: 151992 Hom.: 3536 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.221 AC: 52608 AN: 238002 AF XY: 0.220

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.270

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.231 AC: 326880 AN: 1417252 Hom.: 38709 Cov.: 25 AF XY: 0.229 AC XY: 161980 AN XY: 706726

African (AFR) AF: 0.163 AC: 5154 AN: 31688

American (AMR) AF: 0.236 AC: 9829 AN: 41598

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4326 AN: 25766

East Asian (EAS) AF: 0.307 AC: 11829 AN: 38492

South Asian (SAS) AF: 0.209 AC: 17181 AN: 82224

European-Finnish (FIN) AF: 0.240 AC: 12766 AN: 53204

Middle Eastern (MID) AF: 0.147 AC: 839 AN: 5702

European-Non Finnish (NFE) AF: 0.233 AC: 251639 AN: 1079750

Other (OTH) AF: 0.226 AC: 13317 AN: 58828

GnomAD4 genome AF: 0.213 AC: 32403 AN: 152110 Hom.: 3542 Cov.: 32 AF XY: 0.213 AC XY: 15866 AN XY: 74364

African (AFR) AF: 0.175 AC: 7266 AN: 41504

American (AMR) AF: 0.220 AC: 3368 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3472

East Asian (EAS) AF: 0.274 AC: 1415 AN: 5160

South Asian (SAS) AF: 0.207 AC: 1001 AN: 4828

European-Finnish (FIN) AF: 0.245 AC: 2583 AN: 10560

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15422 AN: 67984

Other (OTH) AF: 0.218 AC: 460 AN: 2114

Alfa AF: 0.221 Hom.: 15567

Bravo AF: 0.213

Asia WGS AF: 0.283 AC: 980 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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	-0.35
CADD	Benign	15
DANN	Benign	0.85
PhyloP100		1.1
PromoterAI		0.0079	Neutral
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.017
dbscSNV1_RF	Benign	0.052
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

Other links and lift over

dbSNP: rs3736242; hg19: chr18-46474746; COSMIC: COSV50989623;