18-48924606-A-G

Variant names:

• chr18-48924606-A-G
• rs7229639
• NM_005904.4:c.743-2696T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005904.4(SMAD7):​c.743-2696T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.872 in 152,184 control chromosomes in the GnomAD database, including 58,018 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.87 (58018 hom., cov: 31)
• Consequence: SMAD7 NM_005904.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.232
• Publications: 48 publications found

Genes affected

SMAD7 (HGNC:6773): (SMAD family member 7) The protein encoded by this gene is a nuclear protein that binds the E3 ubiquitin ligase SMURF2. Upon binding, this complex translocates to the cytoplasm, where it interacts with TGF-beta receptor type-1 (TGFBR1), leading to the degradation of both the encoded protein and TGFBR1. Expression of this gene is induced by TGFBR1. Variations in this gene are a cause of susceptibility to colorectal cancer type 3 (CRCS3). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

SMAD7 Gene-Disease associations (from GenCC):

• colorectal cancer, susceptibility to, 3

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.915 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005904.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD7	NM_005904.4	MANE Select	c.743-2696T>C		intron	N/A	NP_005895.1	O15105-1
	SMAD7	NM_001190821.2		c.740-2696T>C		intron	N/A	NP_001177750.1	O15105-3
	SMAD7	NM_001190823.2		c.179-2696T>C		intron	N/A	NP_001177752.1	B3KYA8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD7	ENST00000262158.8	TSL:1 MANE Select	c.743-2696T>C		intron	N/A	ENSP00000262158.2	O15105-1
	SMAD7	ENST00000589634.1	TSL:4	c.740-2696T>C		intron	N/A	ENSP00000467621.1	O15105-3
	SMAD7	ENST00000911789.1		c.668-2696T>C		intron	N/A	ENSP00000581848.1

Frequencies

GnomAD3 genomes AF: 0.872 AC: 132557 AN: 152066 Hom.: 57994 Cov.: 31

Gnomad AFR AF: 0.805

Gnomad AMI AF: 0.901

Gnomad AMR AF: 0.865

Gnomad ASJ AF: 0.931

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.938

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.956

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.889

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.872 AC: 132634 AN: 152184 Hom.: 58018 Cov.: 31 AF XY: 0.870 AC XY: 64740 AN XY: 74408

African (AFR) AF: 0.805 AC: 33406 AN: 41492

American (AMR) AF: 0.865 AC: 13233 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.931 AC: 3233 AN: 3472

East Asian (EAS) AF: 0.842 AC: 4342 AN: 5158

South Asian (SAS) AF: 0.938 AC: 4525 AN: 4824

European-Finnish (FIN) AF: 0.866 AC: 9191 AN: 10608

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.907 AC: 61725 AN: 68020

Other (OTH) AF: 0.890 AC: 1877 AN: 2110

Alfa AF: 0.896 Hom.: 182063

Bravo AF: 0.863

Asia WGS AF: 0.883 AC: 3071 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.4
DANN	Benign	0.36
PhyloP100		0.23
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: rs7229639; hg19: chr18-46450976;