18-51065650-T-C

Position:

• chr18-51065650-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1347 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.1139+44T>C		intron_variant		ENST00000342988.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.1139+44T>C		intron_variant		5	NM_005359.6	P1

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

GnomAD3 exomes AF: 0.00315 AC: 760 AN: 241376 Hom.: 7 AF XY: 0.00246 AC XY: 321 AN XY: 130464

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 SAS exome AF: 0.000136

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

Gnomad4 AFR exome AF: 0.0285

Gnomad4 AMR exome AF: 0.00415

Gnomad4 ASJ exome AF: 0.00507

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000181

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.000704

Gnomad4 OTH exome AF: 0.00443

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

Gnomad4 AFR AF: 0.0278

Gnomad4 AMR AF: 0.00671

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000781

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00242 Hom.: 0

Bravo AF: 0.0102

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.3
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs28539779; hg19: chr18-48592020;