Variant 18-48950012-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_005904.4(SMAD7):c.413C>T(p.Pro138Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,569,838 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000053 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

SMAD7
NM_005904.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.90

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09020603).

BP6

Variant 18-48950012-G-A is Benign according to our data. Variant chr18-48950012-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2568858.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD7	NM_005904.4 linkuse as main transcript	c.413C>T	p.Pro138Leu	missense_variant	1/4	ENST00000262158.8
SMAD7	NM_001190821.2 linkuse as main transcript	c.413C>T	p.Pro138Leu	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD7	ENST00000262158.8 linkuse as main transcript	c.413C>T	p.Pro138Leu	missense_variant	1/4	1	NM_005904.4	P4	O15105-1
SMAD7	ENST00000589634.1 linkuse as main transcript	c.413C>T	p.Pro138Leu	missense_variant	1/4	4		A1	O15105-3

Frequencies

GnomAD3 genomes

AF:

0.0000528

AC:

AN:

151546

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000392

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

185586

Hom.:

AF XY:

0.00000956

AC XY:

AN XY:

104616

show subpopulations

Gnomad AFR exome

AF:

0.000122

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000564

AC:

AN:

1418292

Hom.:

Cov.:

AF XY:

0.00000426

AC XY:

AN XY:

704750

show subpopulations

Gnomad4 AFR exome

AF:

0.0000658

Gnomad4 AMR exome

AF:

0.0000258

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000843

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000183

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000528

AC:

AN:

151546

Hom.:

Cov.:

AF XY:

0.0000676

AC XY:

AN XY:

73994

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000392

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.0000286

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.55

D;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.090

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

N;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.0

N;.

REVEL

Benign

0.17

Sift

Benign

0.23

T;.

Sift4G

Benign

0.25

T;T

Polyphen

0.0

B;.

Vest4

0.092

MutPred

0.50

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.36

MPC

2.1

ClinPred

0.20

GERP RS

0.99

Varity_R

0.10

gMVP

0.23

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

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