rs2337104

Variant names:

• chr18-48936582-T-C
• rs2337104
• NM_005904.4:c.742+5899A>G

Variant summary

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

The NM_005904.4(SMAD7):​c.742+5899A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 152,112 control chromosomes in the GnomAD database, including 3,635 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 0.16 (3635 hom., cov: 32)
• Consequence: SMAD7 NM_005904.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.714
• Publications: 5 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 (AFR) allele frequency at 95% confidence interval = 0.38 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.742+5899A>G		intron	N/A	NP_005895.1	O15105-1
	SMAD7	NM_001190821.2		c.739+5899A>G		intron	N/A	NP_001177750.1	O15105-3
	SMAD7	NM_001190823.2		c.178+5899A>G		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.742+5899A>G		intron	N/A	ENSP00000262158.2	O15105-1
	SMAD7	ENST00000589634.1	TSL:4	c.739+5899A>G		intron	N/A	ENSP00000467621.1	O15105-3
	SMAD7	ENST00000911789.1		c.667+11802A>G		intron	N/A	ENSP00000581848.1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23767 AN: 151994 Hom.: 3619 Cov.: 32

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0892

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.0472

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0564

Gnomad OTH AF: 0.126

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

GnomAD4 genome AF: 0.157 AC: 23826 AN: 152112 Hom.: 3635 Cov.: 32 AF XY: 0.157 AC XY: 11644 AN XY: 74386

African (AFR) AF: 0.385 AC: 15954 AN: 41436

American (AMR) AF: 0.0890 AC: 1360 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0686 AC: 238 AN: 3470

East Asian (EAS) AF: 0.0471 AC: 244 AN: 5184

South Asian (SAS) AF: 0.311 AC: 1501 AN: 4820

European-Finnish (FIN) AF: 0.0333 AC: 353 AN: 10592

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.0564 AC: 3835 AN: 68010

Other (OTH) AF: 0.129 AC: 273 AN: 2112

Alfa AF: 0.131 Hom.: 2532

Bravo AF: 0.165

Asia WGS AF: 0.196 AC: 683 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	1.8
DANN	Benign	0.33
PhyloP100		-0.71
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: rs2337104; hg19: chr18-46462952;