18-51045117-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005359.6(SMAD4):c.-127-1803T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 151,888 control chromosomes in the GnomAD database, including 9,708 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.35 ( 9707 hom., cov: 32)

Exomes 𝑓: 0.29 ( 1 hom. )

Consequence

SMAD4
NM_005359.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.355

Publications

5 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: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
Myhre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet
generalized juvenile polyposis/juvenile polyposis coli
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005359.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SMAD4	NM_005359.6	MANE Select	c.-127-1803T>G	intron	N/A	NP_005350.1	Q13485
SMAD4	NM_001407041.1		c.-59-1871T>G	intron	N/A	NP_001393970.1	A0A024R274
SMAD4	NM_001407042.1		c.-127-1803T>G	intron	N/A	NP_001393971.1	Q13485

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SMAD4	ENST00000342988.8	TSL:5 MANE Select	c.-127-1803T>G	intron	N/A	ENSP00000341551.3	Q13485
ENSG00000267699	ENST00000590722.2	TSL:2	n.158-1803T>G	intron	N/A	ENSP00000465737.1	E7EUB6
SMAD4	ENST00000714264.1		c.-127-1803T>G	intron	N/A	ENSP00000519545.1	A0AAQ5BHY6

Frequencies

GnomAD3 genomes

AF:

0.353

AC:

53611

AN:

151756

Hom.:

9698

Cov.:

show subpopulations

Gnomad AFR

AF:

0.284

Gnomad AMI

AF:

0.610

Gnomad AMR

AF:

0.371

Gnomad ASJ

AF:

0.403

Gnomad EAS

AF:

0.411

Gnomad SAS

AF:

0.252

Gnomad FIN

AF:

0.398

Gnomad MID

AF:

0.383

Gnomad NFE

AF:

0.380

Gnomad OTH

AF:

0.373

GnomAD4 exome

AF:

0.286

AC:

AN:

Hom.:

AF XY:

0.125

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.286

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.353

AC:

53667

AN:

151874

Hom.:

9707

Cov.:

AF XY:

0.353

AC XY:

26192

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.284

AC:

11780

AN:

41408

American (AMR)

AF:

0.372

AC:

5679

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.403

AC:

1396

AN:

3464

East Asian (EAS)

AF:

0.410

AC:

2118

AN:

5164

South Asian (SAS)

AF:

0.251

AC:

1209

AN:

4816

European-Finnish (FIN)

AF:

0.398

AC:

4187

AN:

10524

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.380

AC:

25834

AN:

67904

Other (OTH)

AF:

0.377

AC:

797

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1757

3514

5271

7028

8785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

518

1036

1554

2072

2590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.345

Hom.:

1198

Bravo

AF:

0.355

Asia WGS

AF:

0.337

AC:

1171

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

5.5

(source)

DANN

Benign

0.65

PhyloP100

0.35

PromoterAI

0.0036

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over