NM_005359.6:c.1447+257T>C

Variant names:

• chr18-51077033-T-C
• rs2298617
• NM_005359.6:c.1447+257T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005359.6(SMAD4):​c.1447+257T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 280,490 control chromosomes in the GnomAD database, including 22,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11734 hom., cov: 31)
  • Exomes 𝑓: 0.41 (10347 hom.)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.767
• Publications: 6 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=-0.89).
• BP6: Variant 18-51077033-T-C is Benign according to our data. Variant chr18-51077033-T-C is described in ClinVar as Benign. ClinVar VariationId is 680785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

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.1447+257T>C		intron	N/A	NP_005350.1
	SMAD4	NM_001407041.1		c.1447+257T>C		intron	N/A	NP_001393970.1
	SMAD4	NM_001407042.1		c.1447+257T>C		intron	N/A	NP_001393971.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	ENST00000342988.8	TSL:5 MANE Select	c.1447+257T>C		intron	N/A	ENSP00000341551.3
	SMAD4	ENST00000591126.5	TSL:1	n.3448+257T>C		intron	N/A
	SMAD4	ENST00000684953.1		n.3076T>C		non_coding_transcript_exon	Exon 7 of 8

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59442 AN: 151832 Hom.: 11713 Cov.: 31

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.413

GnomAD4 exome AF: 0.409 AC: 52513 AN: 128540 Hom.: 10347 Cov.: 3 AF XY: 0.407 AC XY: 26444 AN XY: 64992

African (AFR) AF: 0.411 AC: 1713 AN: 4168

American (AMR) AF: 0.431 AC: 1925 AN: 4468

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 2235 AN: 5270

East Asian (EAS) AF: 0.501 AC: 5607 AN: 11188

South Asian (SAS) AF: 0.289 AC: 1218 AN: 4208

European-Finnish (FIN) AF: 0.411 AC: 2657 AN: 6466

Middle Eastern (MID) AF: 0.370 AC: 255 AN: 690

European-Non Finnish (NFE) AF: 0.399 AC: 33208 AN: 83242

Other (OTH) AF: 0.418 AC: 3695 AN: 8840

GnomAD4 genome AF: 0.392 AC: 59527 AN: 151950 Hom.: 11734 Cov.: 31 AF XY: 0.389 AC XY: 28907 AN XY: 74256

African (AFR) AF: 0.405 AC: 16777 AN: 41444

American (AMR) AF: 0.401 AC: 6125 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1402 AN: 3468

East Asian (EAS) AF: 0.450 AC: 2320 AN: 5158

South Asian (SAS) AF: 0.253 AC: 1219 AN: 4826

European-Finnish (FIN) AF: 0.396 AC: 4172 AN: 10548

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.382 AC: 25959 AN: 67938

Other (OTH) AF: 0.417 AC: 879 AN: 2106

Alfa AF: 0.379 Hom.: 1836

Bravo AF: 0.401

Asia WGS AF: 0.378 AC: 1313 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.3
DANN	Benign	0.72
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

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: rs2298617; hg19: chr18-48603403;