18-51048726-G-T

Variant names:

• chr18-51048726-G-T
• rs1555685159
• NM_005359.6:c.290G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_005359.6(SMAD4):​c.290G>T​(p.Arg97Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R97C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 10.0

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]

ENSG00000267699 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain MH1 (size 124) in uniprot entity SMAD4_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005359.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMAD4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 52 curated benign missense variants. Gene score misZ: 4.1308 (above the threshold of 3.09). Trascript score misZ: 4.9346 (above the threshold of 3.09). GenCC associations: The gene is linked to familial thoracic aortic aneurysm and aortic dissection, generalized juvenile polyposis/juvenile polyposis coli, hereditary hemorrhagic telangiectasia, Myhre syndrome, pulmonary arterial hypertension, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, juvenile polyposis syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 18-51048726-G-T is Pathogenic according to our data. Variant chr18-51048726-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 560163.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.290G>T	p.Arg97Leu	missense_variant	Exon 3 of 12	ENST00000342988.8	NP_005350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.290G>T	p.Arg97Leu	missense_variant	Exon 3 of 12	5	NM_005359.6	ENSP00000341551.3
ENSG00000267699	ENST00000590722.2	n.*313G>T		non_coding_transcript_exon_variant	Exon 4 of 9	2		ENSP00000465737.1
ENSG00000267699	ENST00000590722.2	n.*313G>T		3_prime_UTR_variant	Exon 4 of 9	2		ENSP00000465737.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Heritable Thoracic Aortic Disease Pathogenic:1

Apr 01, 2018

Department of Internal Medicine, The University of Texas McGovern Medical School, The University of Texas Health Science Center at Houston

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant was identified in a family with thoracic aortic disease and no evidence of juvenile polyposis and/or hereditary hemorrhagic telangiectasia -

Heritable thoracic aortic disease without juvenile polyposis and hereditary hemorrhagic telangiectasia Pathogenic:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Juvenile polyposis syndrome Uncertain:1

Jan 20, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with thoracic aortic aneurysm and dissection (PMID: 30809044). ClinVar contains an entry for this variant (Variation ID: 560163). This sequence change replaces arginine with leucine at codon 97 of the SMAD4 protein (p.Arg97Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to affect SMAD4 protein function (PMID: 30809044). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D;D;D;D;D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.3	.;M;.;.;M;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.2	.;D;.;.;D;.;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	.;D;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;D;.;.
Vest4		0.94, 0.93, 0.93
MutPred		0.87		Loss of MoRF binding (P = 0.0228);Loss of MoRF binding (P = 0.0228);Loss of MoRF binding (P = 0.0228);Loss of MoRF binding (P = 0.0228);Loss of MoRF binding (P = 0.0228);Loss of MoRF binding (P = 0.0228);Loss of MoRF binding (P = 0.0228);
MVP		0.97
MPC		3.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs1555685159; hg19: chr18-48575096;