chr18-51067127-A-T

Position:

• chr18-51067127-A-T

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.1248A>T​(p.Arg416Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. Synonymous variant affecting the same amino acid position (i.e. R416R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.789

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 mutagenesis_site No effect on heterotrimerization. Partially diminished transcriptional activation. (size 0) in uniprot entity SMAD4_HUMAN
• 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, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.1248A>T	p.Arg416Ser	missense_variant	10/12	ENST00000342988.8
SMAD4	NM_001407041.1	c.1248A>T	p.Arg416Ser	missense_variant	10/12
SMAD4	NM_001407042.1	c.1248A>T	p.Arg416Ser	missense_variant	10/12
SMAD4	NR_176265.1	n.1786A>T		non_coding_transcript_exon_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.1248A>T	p.Arg416Ser	missense_variant	10/12	5	NM_005359.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251466 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D;D;.
Eigen	Benign	0.19
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.7	D;D;.;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.010	D;D;.;.
Sift4G	Benign	0.091	T;T;T;D
Polyphen		0.37	B;B;.;.
Vest4		0.93
MutPred		0.38		Gain of disorder (P = 0.0639);Gain of disorder (P = 0.0639);.;.;
MVP		1.0
MPC		2.8
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.89
gMVP		0.97

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: rs786202472; hg19: chr18-48593497; COSMIC: COSV61690561;