18-51059974-C-T

Variant names:

• chr18-51059974-C-T
• rs948588
• NM_005359.6:c.955+58C>T

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.955+58C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0713 in 1,271,216 control chromosomes in the GnomAD database, including 3,562 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (266 hom., cov: 32)
  • Exomes 𝑓: 0.074 (3296 hom.)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.748
• Publications: 23 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 18-51059974-C-T is Benign according to our data. Variant chr18-51059974-C-T is described in ClinVar as Benign. ClinVar VariationId is 1253468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0792 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.955+58C>T		intron	N/A	NP_005350.1
	SMAD4	NM_001407041.1		c.955+58C>T		intron	N/A	NP_001393970.1
	SMAD4	NM_001407042.1		c.955+58C>T		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.955+58C>T		intron	N/A	ENSP00000341551.3
	SMAD4	ENST00000591126.5	TSL:1	n.2956+58C>T		intron	N/A
	SMAD4	ENST00000690892.1		n.1121C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0542 AC: 8234 AN: 151920 Hom.: 266 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0476

Gnomad EAS AF: 0.0447

Gnomad SAS AF: 0.0487

Gnomad FIN AF: 0.0858

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0810

Gnomad OTH AF: 0.0344

GnomAD4 exome AF: 0.0737 AC: 82453 AN: 1119178 Hom.: 3296 AF XY: 0.0728 AC XY: 41680 AN XY: 572608

African (AFR) AF: 0.0114 AC: 304 AN: 26710

American (AMR) AF: 0.0195 AC: 863 AN: 44170

Ashkenazi Jewish (ASJ) AF: 0.0569 AC: 1365 AN: 23970

East Asian (EAS) AF: 0.0437 AC: 1660 AN: 38006

South Asian (SAS) AF: 0.0435 AC: 3435 AN: 79028

European-Finnish (FIN) AF: 0.0864 AC: 4560 AN: 52796

Middle Eastern (MID) AF: 0.0278 AC: 142 AN: 5104

European-Non Finnish (NFE) AF: 0.0835 AC: 66811 AN: 800328

Other (OTH) AF: 0.0675 AC: 3313 AN: 49066

GnomAD4 genome AF: 0.0541 AC: 8230 AN: 152038 Hom.: 266 Cov.: 32 AF XY: 0.0533 AC XY: 3959 AN XY: 74292

African (AFR) AF: 0.0147 AC: 609 AN: 41482

American (AMR) AF: 0.0276 AC: 422 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0476 AC: 165 AN: 3470

East Asian (EAS) AF: 0.0443 AC: 229 AN: 5174

South Asian (SAS) AF: 0.0488 AC: 235 AN: 4818

European-Finnish (FIN) AF: 0.0858 AC: 905 AN: 10546

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0810 AC: 5507 AN: 67962

Other (OTH) AF: 0.0341 AC: 72 AN: 2112

Alfa AF: 0.0687 Hom.: 698

Bravo AF: 0.0482

Asia WGS AF: 0.0330 AC: 113 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.53
PhyloP100		-0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs948588; hg19: chr18-48586344; COSMIC: COSV61694712;