18-51065650-T-C

Variant names:

• chr18-51065650-T-C
• rs28539779
• NM_005359.6:c.1139+44T>C

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.1139+44T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,485,646 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (24 hom.)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.520
• Publications: 1 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: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
• Myhre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.8).
• BP6: Variant 18-51065650-T-C is Benign according to our data. Variant chr18-51065650-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1251216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00886 (1347/151994) while in subpopulation AFR AF = 0.0278 (1155/41572). AF 95% confidence interval is 0.0265. There are 18 homozygotes in GnomAd4. There are 637 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1347 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	NM_005359.6	MANE Select	c.1139+44T>C		intron	N/A	NP_005350.1
	SMAD4	NR_176264.1		n.1783T>C		non_coding_transcript_exon	Exon 10 of 10
	SMAD4	NM_001407043.1		c.*37T>C		3_prime_UTR	Exon 9 of 9	NP_001393972.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	ENST00000342988.8	TSL:5 MANE Select	c.1139+44T>C		intron	N/A	ENSP00000341551.3
	SMAD4	ENST00000591126.5	TSL:1	n.3140+44T>C		intron	N/A
	SMAD4	ENST00000688307.1		n.434T>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00875 AC: 1329 AN: 151876 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00672

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000781

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00315 AC: 760 AN: 241376 AF XY: 0.00246

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.00361

Gnomad ASJ exome AF: 0.00524

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000484

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00164 AC: 2192 AN: 1333652 Hom.: 24 Cov.: 19 AF XY: 0.00156 AC XY: 1042 AN XY: 669446

African (AFR) AF: 0.0285 AC: 877 AN: 30728

American (AMR) AF: 0.00415 AC: 179 AN: 43132

Ashkenazi Jewish (ASJ) AF: 0.00507 AC: 127 AN: 25028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39068

South Asian (SAS) AF: 0.000181 AC: 15 AN: 82710

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51892

Middle Eastern (MID) AF: 0.00752 AC: 41 AN: 5452

European-Non Finnish (NFE) AF: 0.000704 AC: 704 AN: 999634

Other (OTH) AF: 0.00443 AC: 248 AN: 56008

GnomAD4 genome AF: 0.00886 AC: 1347 AN: 151994 Hom.: 18 Cov.: 32 AF XY: 0.00857 AC XY: 637 AN XY: 74344

African (AFR) AF: 0.0278 AC: 1155 AN: 41572

American (AMR) AF: 0.00671 AC: 102 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000781 AC: 53 AN: 67880

Other (OTH) AF: 0.0109 AC: 23 AN: 2108

Alfa AF: 0.00372 Hom.: 3

Bravo AF: 0.0102

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.3
DANN	Benign	0.76
PhyloP100		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28539779; hg19: chr18-48592020;