Variant chr18-48948376-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BA1

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

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 made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
SMAD7	NM_005904.4 linkuse as main transcript	c.667+8G>A	splice_region_variant, intron_variant	ENST00000262158.8
SMAD7	NM_001190821.2 linkuse as main transcript	c.667+8G>A	splice_region_variant, intron_variant
SMAD7	NM_001190822.2 linkuse as main transcript	c.22+8G>A	splice_region_variant, intron_variant
SMAD7	XM_047437509.1 linkuse as main transcript	c.22+8G>A	splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
SMAD7	ENST00000262158.8 linkuse as main transcript	c.667+8G>A	splice_region_variant, intron_variant	1	NM_005904.4	P4	O15105-1
SMAD7	ENST00000586093.1 linkuse as main transcript	c.22+8G>A	splice_region_variant, intron_variant	2
SMAD7	ENST00000589634.1 linkuse as main transcript	c.667+8G>A	splice_region_variant, intron_variant	4		A1	O15105-3
SMAD7	ENST00000591805.5 linkuse as main transcript	c.22+8G>A	splice_region_variant, intron_variant	2			O15105-2

Frequencies

GnomAD3 genomes

AF:

0.213

AC:

32373

AN:

151992

Hom.:

3536

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.229

AC XY:

161980

AN XY:

706726

show subpopulations

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.:

AF XY:

0.213

AC XY:

15866

AN XY:

74364

show subpopulations

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: no assertion criteria provided

LINK: link

Submissions by phenotype

SMAD7-related disorder

Benign:1

Likely benign, no assertion criteria provided

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over