chr18-51030711-A-ACGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_005359.6(SMAD4):c.-128+108_-128+110dupGGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0466 in 150,288 control chromosomes in the GnomAD database, including 500 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.047 ( 497 hom., cov: 31)

Exomes 𝑓: 0.012 ( 3 hom. )

Consequence

SMAD4
NM_005359.6 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.545

Publications

1 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 -10 ACMG points.

BP6

Variant 18-51030711-A-ACGG is Benign according to our data. Variant chr18-51030711-A-ACGG is described in ClinVar as Benign. ClinVar VariationId is 1292858.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 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.-128+108_-128+110dupGGC	intron	N/A	NP_005350.1	Q13485
SMAD4	NM_001407041.1		c.-60+455_-60+457dupGGC	intron	N/A	NP_001393970.1	A0A024R274
SMAD4	NM_001407042.1		c.-128+455_-128+457dupGGC	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.-128+88_-128+89insCGG	intron	N/A	ENSP00000341551.3	Q13485
ENSG00000267699	ENST00000590722.2	TSL:2	n.158-16209_158-16208insCGG	intron	N/A	ENSP00000465737.1	E7EUB6
SMAD4	ENST00000714264.1		c.-128+88_-128+89insCGG	intron	N/A	ENSP00000519545.1	A0AAQ5BHY6

Frequencies

GnomAD3 genomes

AF:

0.0468

AC:

6954

AN:

148722

Hom.:

489

Cov.:

show subpopulations

Gnomad AFR

AF:

0.149

Gnomad AMI

AF:

0.00773

Gnomad AMR

AF:

0.0212

Gnomad ASJ

AF:

0.00615

Gnomad EAS

AF:

0.000595

Gnomad SAS

AF:

0.00356

Gnomad FIN

AF:

0.000726

Gnomad MID

AF:

0.00962

Gnomad NFE

AF:

0.00626

Gnomad OTH

AF:

0.0458

GnomAD4 exome

AF:

0.0116

AC:

AN:

1460

Hom.:

AF XY:

0.0159

AC XY:

AN XY:

878

show subpopulations

African (AFR)

AF:

0.750

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00118

AC:

AN:

848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.125

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0219

AC:

AN:

502

Other (OTH)

AF:

0.0385

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.589

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0470

AC:

6993

AN:

148828

Hom.:

497

Cov.:

AF XY:

0.0453

AC XY:

3289

AN XY:

72628

show subpopulations

African (AFR)

AF:

0.149

AC:

6104

AN:

40856

American (AMR)

AF:

0.0211

AC:

318

AN:

15042

Ashkenazi Jewish (ASJ)

AF:

0.00615

AC:

AN:

3416

East Asian (EAS)

AF:

0.000597

AC:

AN:

5022

South Asian (SAS)

AF:

0.00356

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.000726

AC:

AN:

9638

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00626

AC:

418

AN:

66812

Other (OTH)

AF:

0.0458

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

290

580

870

1160

1450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.000627

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.55

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over