chr18-51078455-A-G

Position:

• chr18-51078455-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005359.6(SMAD4):​c.1647A>G​(p.Gln549Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: SMAD4 NM_005359.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.730

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 18-51078455-A-G is Benign according to our data. Variant chr18-51078455-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 231980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-51078455-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000335 (49/1461206) while in subpopulation MID AF= 0.000694 (4/5766). AF 95% confidence interval is 0.000236. There are 0 homozygotes in gnomad4_exome. There are 22 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.1647A>G	p.Gln549Gln	synonymous_variant	12/12	ENST00000342988.8	NP_005350.1
SMAD4	NM_001407041.1	c.1647A>G	p.Gln549Gln	synonymous_variant	12/12		NP_001393970.1
SMAD4	NM_001407042.1	c.1647A>G	p.Gln549Gln	synonymous_variant	12/12		NP_001393971.1
SMAD4	NR_176265.1	n.2298A>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.1647A>G	p.Gln549Gln	synonymous_variant	12/12	5	NM_005359.6	ENSP00000341551.3

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 250984 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135626

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461206 Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22 AN XY: 726910

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74456

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000677 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 21, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2017	The SMAD4 c.1647A>G;p.Gln549Gln variant is listed as likely benign in the ClinVar database (Variation ID: 231980). The variant is listed in the dbSNP variant database (rs113545983) with an allele frequency of 0.0154 percent (2/13004 alleles) in the Exome Variant Server and 0.002849 percent (7/245724 alleles) in the Genome Aggregation Database. The nucleotide at this position is weakly conserved across species and computational algorithms (SpliceSiteFinder-like, MaxEntScan, NNSplice, GeneSplicer, Human Splicing Finder) predict this variant will not alter splicing. One publication indicated that this variant may be associated with poor prognosis in pancreatic cancer, but is not necessarily causative for cancer (Javle 2014). Considering available information, this variant is classified as likely benign. References: Javle M et al. Biomarkers of TGF-ß signaling pathway and prognosis of pancreatic cancer. PLoS One. 2014 Jan 20;9(1):e85942. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	SMAD4: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2017	Variant summary: The c.1647A>G (p.Gln549=) in SMAD4 gene is a synonymous change that involves a non-conserved nucleotide. 4/5 programs in Alamut predict that this variant does not affect the normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population datasets of ExAC and gnomAD at a similar frequencies 0.000028 (3/120978 and 7/245724 chrs tested, respectively). However, the possibility of the variant to be derived from pseudogene cannot be completely ruled out. The variant has not, to our knowledge, been reported in affected individuals via published reports but is cited as Benign/Likely Benign by reputable databases/clinical laboratories. Taking together, the variant was classified as Benign. -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 09, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 31, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2015

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. -

Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2015

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 01, 2023

- -

Juvenile polyposis syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.89
DANN	Benign	0.41

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: rs113545983; hg19: chr18-48604825;