chr18-48946306-G-A

Variant names:

• chr18-48946306-G-A
• rs1316447
• NM_005904.4:c.667+2078C>T

Variant summary

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

The NM_005904.4(SMAD7):​c.667+2078C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 152,036 control chromosomes in the GnomAD database, including 3,219 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 0.20 (3219 hom., cov: 32)
• Consequence: SMAD7 NM_005904.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.976
• Publications: 10 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD7	NM_005904.4	c.667+2078C>T		intron_variant	Intron 2 of 3	ENST00000262158.8	NP_005895.1
SMAD7	NM_001190821.2	c.667+2078C>T		intron_variant	Intron 2 of 3		NP_001177750.1
SMAD7	NM_001190822.2	c.22+2078C>T		intron_variant	Intron 2 of 3		NP_001177751.1
SMAD7	XM_047437509.1	c.22+2078C>T		intron_variant	Intron 2 of 3		XP_047293465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD7	ENST00000262158.8	c.667+2078C>T		intron_variant	Intron 2 of 3	1	NM_005904.4	ENSP00000262158.2
SMAD7	ENST00000589634.1	c.667+2078C>T		intron_variant	Intron 2 of 3	4		ENSP00000467621.1
SMAD7	ENST00000591805.5	c.22+2078C>T		intron_variant	Intron 2 of 3	2		ENSP00000466902.1
SMAD7	ENST00000586093.1	c.22+2078C>T		intron_variant	Intron 1 of 2	2		ENSP00000465590.1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30326 AN: 151918 Hom.: 3215 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.0534

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.236

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

GnomAD4 genome AF: 0.200 AC: 30341 AN: 152036 Hom.: 3219 Cov.: 32 AF XY: 0.196 AC XY: 14531 AN XY: 74316

African (AFR) AF: 0.254 AC: 10522 AN: 41478

American (AMR) AF: 0.176 AC: 2689 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1123 AN: 3466

East Asian (EAS) AF: 0.0533 AC: 276 AN: 5180

South Asian (SAS) AF: 0.155 AC: 749 AN: 4820

European-Finnish (FIN) AF: 0.142 AC: 1499 AN: 10546

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12739 AN: 67948

Other (OTH) AF: 0.236 AC: 499 AN: 2110

Alfa AF: 0.197 Hom.: 5827

Bravo AF: 0.204

Asia WGS AF: 0.111 AC: 388 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.7
DANN	Benign	0.64
PhyloP100		0.98
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: rs1316447; hg19: chr18-46472676;