rs948589

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005359.6(SMAD4):c.905-52A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0697 in 1,374,694 control chromosomes in the GnomAD database, including 3,902 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.052 ( 253 hom., cov: 32)

Exomes 𝑓: 0.072 ( 3649 hom. )

Consequence

SMAD4
NM_005359.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.68

Publications

4 publications found

Variant links:

COSMIC-nc: COSV61694707

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 18-51059814-A-G is Benign according to our data. Variant chr18-51059814-A-G is described in ClinVar as Benign. ClinVar VariationId is 24817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0793 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.905-52A>G	intron	N/A	NP_005350.1	Q13485
SMAD4	NM_001407041.1		c.905-52A>G	intron	N/A	NP_001393970.1	A0A024R274
SMAD4	NM_001407042.1		c.905-52A>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.905-52A>G	intron	N/A	ENSP00000341551.3	Q13485
SMAD4	ENST00000591126.5	TSL:1	n.2906-52A>G	intron	N/A
SMAD4	ENST00000714264.1		c.905-52A>G	intron	N/A	ENSP00000519545.1	A0AAQ5BHY6

Frequencies

GnomAD3 genomes

AF:

0.0525

AC:

7989

AN:

152192

Hom.:

253

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0142

Gnomad AMI

AF:

0.0835

Gnomad AMR

AF:

0.0276

Gnomad ASJ

AF:

0.0476

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0484

Gnomad FIN

AF:

0.0850

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0811

Gnomad OTH

AF:

0.0325

GnomAD4 exome

AF:

0.0718

AC:

87827

AN:

1222384

Hom.:

3649

Cov.:

AF XY:

0.0710

AC XY:

44022

AN XY:

619904

show subpopulations

African (AFR)

AF:

0.0104

AC:

300

AN:

28750

American (AMR)

AF:

0.0194

AC:

860

AN:

44318

Ashkenazi Jewish (ASJ)

AF:

0.0567

AC:

1393

AN:

24556

East Asian (EAS)

AF:

0.00112

AC:

AN:

38530

South Asian (SAS)

AF:

0.0428

AC:

3471

AN:

81130

European-Finnish (FIN)

AF:

0.0863

AC:

4579

AN:

53032

Middle Eastern (MID)

AF:

0.0275

AC:

147

AN:

5340

European-Non Finnish (NFE)

AF:

0.0823

AC:

73637

AN:

894272

Other (OTH)

AF:

0.0648

AC:

3397

AN:

52456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

4140

8280

12420

16560

20700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2356

4712

7068

9424

11780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0524

AC:

7987

AN:

152310

Hom.:

253

Cov.:

AF XY:

0.0512

AC XY:

3817

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0142

AC:

590

AN:

41582

American (AMR)

AF:

0.0275

AC:

421

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0476

AC:

165

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5192

South Asian (SAS)

AF:

0.0484

AC:

234

AN:

4832

European-Finnish (FIN)

AF:

0.0850

AC:

902

AN:

10614

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0811

AC:

5517

AN:

68004

Other (OTH)

AF:

0.0322

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

401

803

1204

1606

2007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0508

Hom.:

Bravo

AF:

0.0462

Asia WGS

AF:

0.0170

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Juvenile polyposis syndrome (1)

Myhre syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

8.3

(source)

DANN

Benign

0.74

PhyloP100

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over