18-51076662-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_005359.6(SMAD4):​c.1333C>G​(p.Arg445Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

SMAD4
NM_005359.6 missense

Scores

9
6
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.89
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMAD4NM_005359.6 linkuse as main transcriptc.1333C>G p.Arg445Gly missense_variant 11/12 ENST00000342988.8 NP_005350.1
SMAD4NM_001407041.1 linkuse as main transcriptc.1333C>G p.Arg445Gly missense_variant 11/12 NP_001393970.1
SMAD4NM_001407042.1 linkuse as main transcriptc.1333C>G p.Arg445Gly missense_variant 11/12 NP_001393971.1
SMAD4NR_176265.1 linkuse as main transcriptn.1871C>G non_coding_transcript_exon_variant 11/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMAD4ENST00000342988.8 linkuse as main transcriptc.1333C>G p.Arg445Gly missense_variant 11/125 NM_005359.6 ENSP00000341551 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.97
D;D;D;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
.;D;D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.81
D;D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Benign
1.6
L;L;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-4.2
D;D;.;.
REVEL
Pathogenic
0.69
Sift
Benign
0.042
D;D;.;.
Sift4G
Benign
0.31
T;T;T;T
Polyphen
0.97
D;D;.;.
Vest4
0.82
MutPred
0.58
Loss of MoRF binding (P = 0.0109);Loss of MoRF binding (P = 0.0109);.;.;
MVP
0.96
MPC
2.0
ClinPred
0.89
D
GERP RS
6.0
Varity_R
0.62
gMVP
0.94

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: chr18-48603032; API