18-51058381-A-G

Position:

• chr18-51058381-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4 BS2

The NM_005359.6(SMAD4):​c.829A>G​(p.Thr277Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.19

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_benign. Variant got -2 ACMG points.

• 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=0.2677548).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.829A>G	p.Thr277Ala	missense_variant	7/12	ENST00000342988.8	NP_005350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.829A>G	p.Thr277Ala	missense_variant	7/12	5	NM_005359.6	ENSP00000341551	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 29, 2016

Variant summary: Variant summary: The SMAD4 c.829A>G (p.Thr277Ala) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121412 control chromosomes and has not been reported in any patients. Multiple functional studies have shown that Thr277 was located in the linker domain and phosphorylated by ERK and GSK3 (Roelen_2003, Demagny_2014). T277A causes loss of phosphorylation and decrease of the TGF-beta/SMAD4 pathway activity (Roelen_2003). All genes associated with a phenotype of HHT (Hereditary Hemorrahagic Telangectasia), which includes SMAD4, are known to be part of the TGF-beta signaling pathway, while SMAD4 also acts as a tumor suppressor in context of the JPC (Juvenile polyposis coli) phenotype. Mutations in several other genes within this pathway, are also known to cause familial thoracic aneurisms and aortic dissections. Taken together, this variant is classified as a variant of uncertain clinical significance (VUS) unless additional clinical and functional information to unequivocally establish its outcome are obtained. -

Juvenile polyposis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 17, 2021

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD4 protein function. This variant has not been reported in the literature in individuals with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 496291). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 277 of the SMAD4 protein (p.Thr277Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D;D
Eigen	Benign	-0.0049
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	.;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.18
Sift	Benign	0.29	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.13	B;B
Vest4		0.27
MutPred		0.12		Loss of glycosylation at T277 (P = 0.0076);Loss of glycosylation at T277 (P = 0.0076);
MVP		0.62
MPC		0.45
ClinPred		0.52	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555685960; hg19: chr18-48584751;