chr18-48939295-A-G

Variant names:

• chr18-48939295-A-G
• rs4939832
• NM_005904.4:c.742+3186T>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.742+3186T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 150,992 control chromosomes in the GnomAD database, including 8,143 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 0.31 (8143 hom., cov: 28)
• Consequence: SMAD7 NM_005904.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.750
• Publications: 13 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=-0.53).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.481 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+3186T>C		intron	N/A	NP_005895.1	O15105-1
	SMAD7	NM_001190821.2		c.739+3186T>C		intron	N/A	NP_001177750.1	O15105-3
	SMAD7	NM_001190823.2		c.178+3186T>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.742+3186T>C		intron	N/A	ENSP00000262158.2	O15105-1
	SMAD7	ENST00000589634.1	TSL:4	c.739+3186T>C		intron	N/A	ENSP00000467621.1	O15105-3
	SMAD7	ENST00000911789.1		c.667+9089T>C		intron	N/A	ENSP00000581848.1

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47317 AN: 150872 Hom.: 8120 Cov.: 28

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.393

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.307

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

GnomAD4 genome AF: 0.314 AC: 47376 AN: 150992 Hom.: 8143 Cov.: 28 AF XY: 0.319 AC XY: 23482 AN XY: 73704

African (AFR) AF: 0.434 AC: 17797 AN: 41014

American (AMR) AF: 0.278 AC: 4228 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 848 AN: 3468

East Asian (EAS) AF: 0.392 AC: 1991 AN: 5074

South Asian (SAS) AF: 0.497 AC: 2376 AN: 4776

European-Finnish (FIN) AF: 0.266 AC: 2753 AN: 10344

Middle Eastern (MID) AF: 0.281 AC: 82 AN: 292

European-Non Finnish (NFE) AF: 0.243 AC: 16463 AN: 67838

Other (OTH) AF: 0.313 AC: 654 AN: 2092

Alfa AF: 0.270 Hom.: 18780

Bravo AF: 0.317

Asia WGS AF: 0.498 AC: 1730 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.0
DANN	Benign	0.78
PhyloP100		-0.75
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: rs4939832; hg19: chr18-46465665;