18-51076671-C-G

Position:

• chr18-51076671-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_005359.6(SMAD4):​c.1342C>G​(p.Gln448Glu) 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q448K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.77

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain MH2 (size 229) in uniprot entity SMAD4_HUMAN there are 81 pathogenic changes around while only 3 benign (96%) in NM_005359.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMAD4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.1342C>G	p.Gln448Glu	missense_variant	11/12	ENST00000342988.8
SMAD4	NM_001407041.1	c.1342C>G	p.Gln448Glu	missense_variant	11/12
SMAD4	NM_001407042.1	c.1342C>G	p.Gln448Glu	missense_variant	11/12
SMAD4	NR_176265.1	n.1880C>G		non_coding_transcript_exon_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.1342C>G	p.Gln448Glu	missense_variant	11/12	5	NM_005359.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2021

The p.Q448E variant (also known as c.1342C>G), located in coding exon 10 of the SMAD4 gene, results from a C to G substitution at nucleotide position 1342. The glutamine at codon 448 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Juvenile polyposis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 12, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 662465). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 448 of the SMAD4 protein (p.Gln448Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D;D;D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.9	L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.0	N;N;.;.
REVEL	Pathogenic	0.71
Sift	Benign	0.17	T;T;.;.
Sift4G	Benign	0.74	T;T;T;T
Polyphen		0.96	D;D;.;.
Vest4		0.69
MutPred		0.61		Loss of MoRF binding (P = 0.0384);Loss of MoRF binding (P = 0.0384);.;.;
MVP		0.88
MPC		2.2
ClinPred		0.71	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.93

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: rs377767361; hg19: chr18-48603041;