rs3736242

chr18-48948376-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate 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 (★).

• 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 criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.12

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 -12 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 id is 3060367.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD7	NM_005904.4	c.667+8G>A		splice_region_variant, intron_variant		ENST00000262158.8
SMAD7	NM_001190821.2	c.667+8G>A		splice_region_variant, intron_variant
SMAD7	NM_001190822.2	c.22+8G>A		splice_region_variant, intron_variant
SMAD7	XM_047437509.1	c.22+8G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD7	ENST00000262158.8	c.667+8G>A		splice_region_variant, intron_variant		1	NM_005904.4	P4
SMAD7	ENST00000586093.1	c.22+8G>A		splice_region_variant, intron_variant		2
SMAD7	ENST00000589634.1	c.667+8G>A		splice_region_variant, intron_variant		4		A1
SMAD7	ENST00000591805.5	c.22+8G>A		splice_region_variant, intron_variant		2

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

GnomAD3 exomes AF: 0.221 AC: 52608 AN: 238002 Hom.: 5949 AF XY: 0.220 AC XY: 28380 AN XY: 128964

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 SAS exome AF: 0.210

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

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.236

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.307

Gnomad4 SAS exome AF: 0.209

Gnomad4 FIN exome AF: 0.240

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.226

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

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.274

Gnomad4 SAS AF: 0.207

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.227

Gnomad4 OTH AF: 0.218

Alfa AF: 0.220 Hom.: 7185

Bravo AF: 0.213

Asia WGS AF: 0.283 AC: 980 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SMAD7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2020

This variant is classified as likely 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	-0.35
Cadd	Benign	15
Dann	Benign	0.85

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

Publications

LitVar

Other links and lift over

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