rs1555687613

Positions:

• chr18-51078453-C-A
• chr18-51078453-C-G
• chr18-51078453-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_005359.6(SMAD4):​c.1645C>A​(p.Gln549Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q549Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain MH2 (size 229) in uniprot entity SMAD4_HUMAN there are 40 pathogenic changes around while only 2 benign (95%) in NM_005359.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMAD4. . Gene score misZ 4.1308 (greater than the threshold 3.09). Trascript score misZ 4.9346 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26149696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.1645C>A	p.Gln549Lys	missense_variant	12/12	ENST00000342988.8	NP_005350.1
SMAD4	NM_001407041.1	c.1645C>A	p.Gln549Lys	missense_variant	12/12		NP_001393970.1
SMAD4	NM_001407042.1	c.1645C>A	p.Gln549Lys	missense_variant	12/12		NP_001393971.1
SMAD4	NR_176265.1	n.2296C>A		non_coding_transcript_exon_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.1645C>A	p.Gln549Lys	missense_variant	12/12	5	NM_005359.6	ENSP00000341551	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

Apr 13, 2021

The p.Q549K variant (also known as c.1645C>A), located in coding exon 11 of the SMAD4 gene, results from a C to A substitution at nucleotide position 1645. The glutamine at codon 549 is replaced by lysine, an amino acid with similar properties. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.44	T;T;T
Eigen	Benign	-0.072
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	-0.51	N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.57	T;T;.
Sift4G	Benign	0.87	T;T;T
Polyphen		0.018	B;B;.
Vest4		0.42
MutPred		0.24		Gain of methylation at Q549 (P = 0.0044);Gain of methylation at Q549 (P = 0.0044);.;
MVP		0.93
MPC		1.9
ClinPred		0.42	T
GERP RS		6.0
Varity_R		0.31
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-48604823;