18-51077033-T-C

Variant names:

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.1447+257T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 280,490 control chromosomes in the GnomAD database, including 22,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 11734 hom., cov: 31)

Exomes 𝑓: 0.41 ( 10347 hom. )

Consequence

SMAD4
NM_005359.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.767

Publications

6 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:

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=-0.89).

BP6

Variant 18-51077033-T-C is Benign according to our data. Variant chr18-51077033-T-C is described in ClinVar as Benign. ClinVar VariationId is 680785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 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.1447+257T>C	intron	N/A	NP_005350.1	Q13485
SMAD4	NM_001407041.1		c.1447+257T>C	intron	N/A	NP_001393970.1	A0A024R274
SMAD4	NM_001407042.1		c.1447+257T>C	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.1447+257T>C	intron	N/A	ENSP00000341551.3	Q13485
SMAD4	ENST00000591126.5	TSL:1	n.3448+257T>C	intron	N/A
SMAD4	ENST00000593223.2	TSL:3	c.*222T>C	3_prime_UTR	Exon 11 of 11	ENSP00000466118.2	K7ELK2

Frequencies

GnomAD3 genomes

AF:

0.391

AC:

59442

AN:

151832

Hom.:

11713

Cov.:

show subpopulations

Gnomad AFR

AF:

0.404

Gnomad AMI

AF:

0.612

Gnomad AMR

AF:

0.401

Gnomad ASJ

AF:

0.404

Gnomad EAS

AF:

0.450

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.396

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.382

Gnomad OTH

AF:

0.413

GnomAD4 exome

AF:

0.409

AC:

52513

AN:

128540

Hom.:

10347

Cov.:

AF XY:

0.407

AC XY:

26444

AN XY:

64992

show subpopulations

African (AFR)

AF:

0.411

AC:

1713

AN:

4168

American (AMR)

AF:

0.431

AC:

1925

AN:

4468

Ashkenazi Jewish (ASJ)

AF:

0.424

AC:

2235

AN:

5270

East Asian (EAS)

AF:

0.501

AC:

5607

AN:

11188

South Asian (SAS)

AF:

0.289

AC:

1218

AN:

4208

European-Finnish (FIN)

AF:

0.411

AC:

2657

AN:

6466

Middle Eastern (MID)

AF:

0.370

AC:

255

AN:

690

European-Non Finnish (NFE)

AF:

0.399

AC:

33208

AN:

83242

Other (OTH)

AF:

0.418

AC:

3695

AN:

8840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1535

3070

4606

6141

7676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

186

372

558

744

930

<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:

0.392

AC:

59527

AN:

151950

Hom.:

11734

Cov.:

AF XY:

0.389

AC XY:

28907

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.405

AC:

16777

AN:

41444

American (AMR)

AF:

0.401

AC:

6125

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.404

AC:

1402

AN:

3468

East Asian (EAS)

AF:

0.450

AC:

2320

AN:

5158

South Asian (SAS)

AF:

0.253

AC:

1219

AN:

4826

European-Finnish (FIN)

AF:

0.396

AC:

4172

AN:

10548

Middle Eastern (MID)

AF:

0.395

AC:

116

AN:

294

European-Non Finnish (NFE)

AF:

0.382

AC:

25959

AN:

67938

Other (OTH)

AF:

0.417

AC:

879

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1834

3667

5501

7334

9168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<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:

0.379

Hom.:

1836

Bravo

AF:

0.401

Asia WGS

AF:

0.378

AC:

1313

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.3

(source)

DANN

Benign

0.72

PhyloP100

-0.77

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

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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