chr18-51030711-A-ACGG

Position:

• chr18-51030711-A-ACGG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005359.6(SMAD4):​c.-128+108_-128+110dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0466 in 150,288 control chromosomes in the GnomAD database, including 500 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.047 (497 hom., cov: 31)
  • Exomes 𝑓: 0.012 (3 hom.)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.545

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 18-51030711-A-ACGG is Benign according to our data. Variant chr18-51030711-A-ACGG is described in ClinVar as [Benign]. Clinvar id is 1292858.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.-128+108_-128+110dup		intron_variant		ENST00000342988.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.-128+108_-128+110dup		intron_variant		5	NM_005359.6	P1

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 6954 AN: 148722 Hom.: 489 Cov.: 31

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00773

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.00615

Gnomad EAS AF: 0.000595

Gnomad SAS AF: 0.00356

Gnomad FIN AF: 0.000726

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.00626

Gnomad OTH AF: 0.0458

GnomAD4 exome AF: 0.0116 AC: 17 AN: 1460 Hom.: 3 AF XY: 0.0159 AC XY: 14 AN XY: 878

Gnomad4 AFR exome AF: 0.750

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0219

Gnomad4 OTH exome AF: 0.0385

GnomAD4 genome AF: 0.0470 AC: 6993 AN: 148828 Hom.: 497 Cov.: 31 AF XY: 0.0453 AC XY: 3289 AN XY: 72628

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.0211

Gnomad4 ASJ AF: 0.00615

Gnomad4 EAS AF: 0.000597

Gnomad4 SAS AF: 0.00356

Gnomad4 FIN AF: 0.000726

Gnomad4 NFE AF: 0.00626

Gnomad4 OTH AF: 0.0458

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs533316618; hg19: chr18-48557081;