Variant chr18-48948426-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005904.4(SMAD7):c.625C>T(p.Pro209Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000762 in 1,443,492 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P209T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

SMAD7
NM_005904.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.12

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 Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SMAD7	NM_005904.4 linkuse as main transcript	c.625C>T	p.Pro209Ser	missense_variant	2/4	ENST00000262158.8
SMAD7	NM_001190821.2 linkuse as main transcript	c.625C>T	p.Pro209Ser	missense_variant	2/4
SMAD7	NM_001190822.2 linkuse as main transcript	c.-21C>T		5_prime_UTR_variant	2/4
SMAD7	XM_047437509.1 linkuse as main transcript	c.-21C>T		5_prime_UTR_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD7	ENST00000262158.8 linkuse as main transcript	c.625C>T	p.Pro209Ser	missense_variant	2/4	1	NM_005904.4	P4	O15105-1
SMAD7	ENST00000589634.1 linkuse as main transcript	c.625C>T	p.Pro209Ser	missense_variant	2/4	4		A1	O15105-3
SMAD7	ENST00000586093.1 linkuse as main transcript	c.-21C>T		5_prime_UTR_variant	1/3	2
SMAD7	ENST00000591805.5 linkuse as main transcript	c.-21C>T		5_prime_UTR_variant	2/4	2			O15105-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000865

AC:

AN:

231092

Hom.:

AF XY:

0.0000159

AC XY:

AN XY:

125552

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000925

Gnomad OTH exome

AF:

0.000179

GnomAD4 exome

AF:

0.00000762

AC:

AN:

1443492

Hom.:

Cov.:

AF XY:

0.00000696

AC XY:

AN XY:

718176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000312

Gnomad4 AMR exome

AF:

0.0000245

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000634

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.625C>T (p.P209S) alteration is located in exon 2 (coding exon 2) of the SMAD7 gene. This alteration results from a C to T substitution at nucleotide position 625, causing the proline (P) at amino acid position 209 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.58

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.8

D;.

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.059

T;T

Polyphen

0.77

P;.

Vest4

0.59

MutPred

0.31

Loss of catalytic residue at P209 (P = 0.0076);Loss of catalytic residue at P209 (P = 0.0076);

MVP

0.84

MPC

2.1

ClinPred

0.99

GERP RS

5.0

Varity_R

0.91

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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