chr18-51078308-A-G

Position:

• chr18-51078308-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_005359.6(SMAD4):​c.1500A>G​(p.Ile500Met) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I500T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2 O:2
• Conservation: PhyloP100: -1.25

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a strand (size 6) in uniprot entity SMAD4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005359.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-51078307-T-C is described in Lovd as [Pathogenic].
• 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, 0.905
• PP5: Variant 18-51078308-A-G is Pathogenic according to our data. Variant chr18-51078308-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 30151.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-51078308-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.1500A>G	p.Ile500Met	missense_variant	12/12	ENST00000342988.8	NP_005350.1
SMAD4	NM_001407041.1	c.1500A>G	p.Ile500Met	missense_variant	12/12		NP_001393970.1
SMAD4	NM_001407042.1	c.1500A>G	p.Ile500Met	missense_variant	12/12		NP_001393971.1
SMAD4	NR_176265.1	n.2151A>G		non_coding_transcript_exon_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.1500A>G	p.Ile500Met	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: Pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Myhre syndrome Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	Unit U781; INSERM (Institut National de la Santé Et de la Recherche Médicale)	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 11, 2011	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D;D;D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.4	N;N;.
REVEL	Pathogenic	0.69
Sift	Benign	0.10	T;T;.
Sift4G	Benign	0.14	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.84
MutPred		0.65		Gain of MoRF binding (P = 0.0725);Gain of MoRF binding (P = 0.0725);.;
MVP		0.99
MPC		2.8
ClinPred		0.89	D
GERP RS		-6.2
Varity_R		0.67
gMVP		0.85

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: rs281875320; hg19: chr18-48604678;