Variant 18-51059974-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.748

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 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 id is 1253468.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-51059974-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6 linkuse as main transcript	c.955+58C>T		intron_variant		ENST00000342988.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8 linkuse as main transcript	c.955+58C>T		intron_variant		5	NM_005359.6	P1

Frequencies

GnomAD3 genomes

AF:

0.0542

AC:

8234

AN:

151920

Hom.:

266

Cov.:

show subpopulations

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

show subpopulations

Gnomad4 AFR exome

AF:

0.0114

Gnomad4 AMR exome

AF:

0.0195

Gnomad4 ASJ exome

AF:

0.0569

Gnomad4 EAS exome

AF:

0.0437

Gnomad4 SAS exome

AF:

0.0435

Gnomad4 FIN exome

AF:

0.0864

Gnomad4 NFE exome

AF:

0.0835

Gnomad4 OTH exome

AF:

0.0675

GnomAD4 genome

AF:

0.0541

AC:

8230

AN:

152038

Hom.:

266

Cov.:

AF XY:

0.0533

AC XY:

3959

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0147

Gnomad4 AMR

AF:

0.0276

Gnomad4 ASJ

AF:

0.0476

Gnomad4 EAS

AF:

0.0443

Gnomad4 SAS

AF:

0.0488

Gnomad4 FIN

AF:

0.0858

Gnomad4 NFE

AF:

0.0810

Gnomad4 OTH

AF:

0.0341

Alfa

AF:

0.0709

Hom.:

584

Bravo

AF:

0.0482

Asia WGS

AF:

0.0330

AC:

113

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.4

DANN

Benign

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over