18-48927678-A-G

Variant names:

• chr18-48927678-A-G
• rs7226855
• NM_005904.4:c.743-5768T>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.743-5768T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 152,002 control chromosomes in the GnomAD database, including 21,088 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 0.52 (21088 hom., cov: 32)
• Consequence: SMAD7 NM_005904.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 22 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 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.743-5768T>C		intron	N/A	NP_005895.1	O15105-1
	SMAD7	NM_001190821.2		c.740-5768T>C		intron	N/A	NP_001177750.1	O15105-3
	SMAD7	NM_001190823.2		c.179-5768T>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.743-5768T>C		intron	N/A	ENSP00000262158.2	O15105-1
	SMAD7	ENST00000589634.1	TSL:4	c.740-5768T>C		intron	N/A	ENSP00000467621.1	O15105-3
	SMAD7	ENST00000911789.1		c.668-5768T>C		intron	N/A	ENSP00000581848.1

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79260 AN: 151884 Hom.: 21049 Cov.: 32

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.452

Gnomad AMR AF: 0.604

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.701

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.503

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

GnomAD4 genome AF: 0.522 AC: 79347 AN: 152002 Hom.: 21088 Cov.: 32 AF XY: 0.530 AC XY: 39370 AN XY: 74302

African (AFR) AF: 0.546 AC: 22626 AN: 41448

American (AMR) AF: 0.605 AC: 9250 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1548 AN: 3470

East Asian (EAS) AF: 0.701 AC: 3619 AN: 5162

South Asian (SAS) AF: 0.698 AC: 3367 AN: 4822

European-Finnish (FIN) AF: 0.501 AC: 5281 AN: 10546

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 32022 AN: 67948

Other (OTH) AF: 0.509 AC: 1075 AN: 2110

Alfa AF: 0.489 Hom.: 30941

Bravo AF: 0.528

Asia WGS AF: 0.689 AC: 2393 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.097
DANN	Benign	0.58
PhyloP100		-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: rs7226855; hg19: chr18-46454048;