18-51030711-A-ACGG

Variant names:

• chr18-51030711-A-ACGG
• rs533316618
• NM_005359.6:c.-128+108_-128+110dupGGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.545
• Publications: 1 publications found

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

ENSG00000267699 (HGNC:):

ACMG classification

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.-128+108_-128+110dupGGC		intron_variant	Intron 1 of 11	ENST00000342988.8	NP_005350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.-128+88_-128+89insCGG		intron_variant	Intron 1 of 11	5	NM_005359.6	ENSP00000341551.3
ENSG00000267699	ENST00000590722.2	n.158-16209_158-16208insCGG		intron_variant	Intron 2 of 8	2		ENSP00000465737.1

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 6954 AN: 148722 Hom.: 489 Cov.: 31

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: 17 AN: 1460 Hom.: 3 AF XY: 0.0159 AC XY: 14 AN XY: 878

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 58

South Asian (SAS) AF: 0.00118 AC: 1 AN: 848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.125 AC: 1 AN: 8

European-Non Finnish (NFE) AF: 0.0219 AC: 11 AN: 502

Other (OTH) AF: 0.0385 AC: 1 AN: 26

GnomAD4 genome AF: 0.0470 AC: 6993 AN: 148828 Hom.: 497 Cov.: 31 AF XY: 0.0453 AC XY: 3289 AN XY: 72628

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: 21 AN: 3416

East Asian (EAS) AF: 0.000597 AC: 3 AN: 5022

South Asian (SAS) AF: 0.00356 AC: 17 AN: 4772

European-Finnish (FIN) AF: 0.000726 AC: 7 AN: 9638

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.00626 AC: 418 AN: 66812

Other (OTH) AF: 0.0458 AC: 95 AN: 2074

Alfa AF: 0.000627 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs533316618; hg19: chr18-48557081;