18-51058432-A-G

Position:

chr18-51058432-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_005359.6(SMAD4):c.880A>G(p.Met294Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000993 in 1,610,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

SMAD4
NM_005359.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10O:1

Conservation

PhyloP100: 4.83

Variant links:

Genes affected

SMAD4 (HGNC:6770): (SMAD family member 4) This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasing blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome. [provided by RefSeq, May 2022]

SMAD4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMAD4. . Gene score misZ 4.1308 (greater than the threshold 3.09). Trascript score misZ 4.9346 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, generalized juvenile polyposis/juvenile polyposis coli, hereditary hemorrhagic telangiectasia, Myhre syndrome, pulmonary arterial hypertension, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, juvenile polyposis syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.058004946).

BP6

Variant 18-51058432-A-G is Benign according to our data. Variant chr18-51058432-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135244.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, not_provided=1, Benign=1, Uncertain_significance=2}. Variant chr18-51058432-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000469 (70/149332) while in subpopulation AFR AF= 0.00158 (64/40526). AF 95% confidence interval is 0.00127. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD4	NM_005359.6 linkuse as main transcript	c.880A>G	p.Met294Val	missense_variant	7/12	ENST00000342988.8	NP_005350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8 linkuse as main transcript	c.880A>G	p.Met294Val	missense_variant	7/12	5	NM_005359.6	ENSP00000341551	P1

Frequencies

GnomAD3 genomes

AF:

0.000469

AC:

AN:

149308

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00158

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000200

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

251476

Hom.:

AF XY:

0.0000956

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1461596

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00158

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000469

AC:

AN:

149332

Hom.:

Cov.:

AF XY:

0.000440

AC XY:

AN XY:

72654

show subpopulations

Gnomad4 AFR

AF:

0.00158

Gnomad4 AMR

AF:

0.000200

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000213

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000296

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000604

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2019	Variant summary: SMAD4 c.880A>G (p.Met294Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 282090 control chromosomes, predominantly at a frequency of 0.0016 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 800 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD4 causing Juvenile Polyposis Syndrome phenotype (2e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.880A>G, was reported in one patient who underwent genetics testing for Lynch syndrome, however without strong evidence for pathogenicity (Yurgelun_2015). The report does not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant three times as likely benign and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 10, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	May 12, 2022	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	This variant is associated with the following publications: (PMID: 24728327, 25980754, 22843233) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2020	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 11, 2021	- -

SMAD4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2021

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). -

Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2018

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. -

Generalized juvenile polyposis/juvenile polyposis coli

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Apr 27, 2018

- -

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Apr 10, 2023

This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -

Juvenile polyposis syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.47

T;T

Eigen

Benign

0.011

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.79

.;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.058

T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

0.97

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.96

N;N

REVEL

Uncertain

0.35

Sift

Benign

0.38

T;T

Sift4G

Benign

0.72

T;T

Polyphen

0.0010

B;B

Vest4

0.47

MVP

0.89

MPC

0.47

ClinPred

0.041

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.41

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