18-51041901-G-A

Variant names:

• chr18-51041901-G-A
• rs10502913
• NM_005359.6:c.-127-5019G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005359.6(SMAD4):​c.-127-5019G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 152,120 control chromosomes in the GnomAD database, including 3,599 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 0.19 (3599 hom., cov: 32)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.309
• Publications: 23 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.-127-5019G>A		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.-127-5019G>A		intron_variant	Intron 1 of 11	5	NM_005359.6	ENSP00000341551.3
ENSG00000267699	ENST00000590722.2	n.158-5019G>A		intron_variant	Intron 2 of 8	2		ENSP00000465737.1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29549 AN: 152000 Hom.: 3595 Cov.: 32

Gnomad AFR AF: 0.0508

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.237

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.194 AC: 29563 AN: 152120 Hom.: 3599 Cov.: 32 AF XY: 0.196 AC XY: 14550 AN XY: 74374

African (AFR) AF: 0.0506 AC: 2101 AN: 41518

American (AMR) AF: 0.259 AC: 3958 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 881 AN: 3466

East Asian (EAS) AF: 0.317 AC: 1641 AN: 5172

South Asian (SAS) AF: 0.186 AC: 897 AN: 4824

European-Finnish (FIN) AF: 0.246 AC: 2598 AN: 10564

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16473 AN: 67978

Other (OTH) AF: 0.242 AC: 512 AN: 2112

Alfa AF: 0.226 Hom.: 763

Bravo AF: 0.195

Asia WGS AF: 0.268 AC: 930 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	5.0
DANN	Benign	0.37
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10502913; hg19: chr18-48568271;