NM_005359.6:c.132A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6BP7BS1

The NM_005359.6(SMAD4):c.132A>G(p.Val44Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,260 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). Synonymous variant affecting the same amino acid position (i.e. V44V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Consequence

SMAD4
NM_005359.6 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.0820

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
Myhre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
generalized juvenile polyposis/juvenile polyposis coli
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
juvenile polyposis syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary hemorrhagic telangiectasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pulmonary arterial hypertension
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SMAD4 links:

ENSG00000267699 (HGNC:):

ENSG00000267699 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 18-51047178-A-G is Benign according to our data. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652. Variant chr18-51047178-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 382652.

BP7

Synonymous conserved (PhyloP=-0.082 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000197 (3/152260) while in subpopulation AFR AF = 0.0000723 (3/41480). AF 95% confidence interval is 0.0000192. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD4	NM_005359.6 link	c.132A>G	p.Val44Val	synonymous_variant	Exon 2 of 12	ENST00000342988.8	NP_005350.1	Q13485A0A024R274

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMAD4	ENST00000342988.8 link	c.132A>G	p.Val44Val	synonymous_variant	Exon 2 of 12	5	NM_005359.6	ENSP00000341551.3	Q13485
ENSG00000267699	ENST00000590722.2 link	n.*155A>G		non_coding_transcript_exon_variant	Exon 3 of 9	2		ENSP00000465737.1	E7EUB6
ENSG00000267699	ENST00000590722.2 link	n.*155A>G		3_prime_UTR_variant	Exon 3 of 9	2		ENSP00000465737.1	E7EUB6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41480

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Jun 30, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2022

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Benign:2

Mar 18, 2025

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Jun 08, 2023

All of Us Research Program, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Apr 19, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jun 06, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Juvenile polyposis syndrome

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

6.9

(source)

DANN

Benign

0.67

PhyloP100

-0.082

PromoterAI

0.0048

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over