18-51078478-C-T

Variant names:

• chr18-51078478-C-T
• rs11663402
• NM_005359.6:c.*11C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005359.6(SMAD4):​c.*11C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 1,588,848 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (55 hom.)
• Consequence: SMAD4 NM_005359.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.135
• Publications: 3 publications found

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]

SMAD4 Gene-Disease associations (from GenCC):

• juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Myhre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• generalized juvenile polyposis/juvenile polyposis coli

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• juvenile polyposis syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 18-51078478-C-T is Benign according to our data. Variant chr18-51078478-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00524 (798/152264) while in subpopulation AMR AF = 0.0083 (127/15298). AF 95% confidence interval is 0.00748. There are 6 homozygotes in GnomAd4. There are 384 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 798 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005359.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	NM_005359.6	MANE Select	c.*11C>T		3_prime_UTR	Exon 12 of 12	NP_005350.1	Q13485
	SMAD4	NM_001407041.1		c.*11C>T		3_prime_UTR	Exon 12 of 12	NP_001393970.1	A0A024R274
	SMAD4	NM_001407042.1		c.*11C>T		3_prime_UTR	Exon 12 of 12	NP_001393971.1	Q13485

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	ENST00000342988.8	TSL:5 MANE Select	c.*11C>T		3_prime_UTR	Exon 12 of 12	ENSP00000341551.3	Q13485
	SMAD4	ENST00000591126.5	TSL:1	n.3671C>T		non_coding_transcript_exon	Exon 8 of 8
	SMAD4	ENST00000714264.1		c.*11C>T		3_prime_UTR	Exon 12 of 12	ENSP00000519545.1	A0AAQ5BHY6

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 798 AN: 152146 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00804

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00519 AC: 1296 AN: 249762 AF XY: 0.00500

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.00516

Gnomad ASJ exome AF: 0.00749

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00356

Gnomad NFE exome AF: 0.00791

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00628 AC: 9027 AN: 1436584 Hom.: 55 Cov.: 26 AF XY: 0.00616 AC XY: 4412 AN XY: 716332

African (AFR) AF: 0.00106 AC: 35 AN: 32898

American (AMR) AF: 0.00513 AC: 229 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00624 AC: 162 AN: 25948

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39570

South Asian (SAS) AF: 0.000513 AC: 44 AN: 85744

European-Finnish (FIN) AF: 0.00468 AC: 248 AN: 52938

Middle Eastern (MID) AF: 0.00297 AC: 17 AN: 5732

European-Non Finnish (NFE) AF: 0.00726 AC: 7914 AN: 1089532

Other (OTH) AF: 0.00633 AC: 377 AN: 59576

GnomAD4 genome AF: 0.00524 AC: 798 AN: 152264 Hom.: 6 Cov.: 32 AF XY: 0.00516 AC XY: 384 AN XY: 74456

African (AFR) AF: 0.00132 AC: 55 AN: 41544

American (AMR) AF: 0.00830 AC: 127 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00804 AC: 547 AN: 68020

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00686 Hom.: 7

Bravo AF: 0.00494

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	1	Carcinoma of colon (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Generalized juvenile polyposis/juvenile polyposis coli (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (1)
-	-	1	Myhre syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.79
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs11663402; hg19: chr18-48604848; COSMIC: COSV104419368; COSMIC: COSV104419368;