rs1060500736

chr18-51054967-T-Achr18-51054967-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_005359.6(SMAD4):c.641T>A(p.Phe214Tyr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F214L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.62

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMAD4
• BP4: Computational evidence support a benign effect (MetaRNN=0.2835028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.641T>A	p.Phe214Tyr	missense_variant	5/12	ENST00000342988.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.641T>A	p.Phe214Tyr	missense_variant	5/12	5	NM_005359.6	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

Juvenile polyposis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2016

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. 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, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMAD4-related disease. This sequence change replaces phenylalanine with tyrosine at codon 214 of the SMAD4 protein (p.Phe214Tyr). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	22
Dann	Benign	0.90
DEOGEN2	Benign	0.39	T;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.3	L;L;.
MutationTaster	Benign	0.99	D;D;D;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.29	N;N;.
REVEL	Benign	0.22
Sift	Benign	1.0	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.94	P;P;.
Vest4		0.50
MutPred		0.26		Gain of phosphorylation at F214 (P = 0.032);Gain of phosphorylation at F214 (P = 0.032);Gain of phosphorylation at F214 (P = 0.032);
MVP		0.75
MPC		0.52
ClinPred		0.66	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.35

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: rs1060500736; hg19: chr18-48581337;