18-48921591-C-A

Variant names:

• chr18-48921591-C-A
• rs780863704
• NM_005904.4:c.1062G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_005904.4(SMAD7):​c.1062G>T​(p.Thr354Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T354T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMAD7 NM_005904.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP7: Synonymous conserved (PhyloP=2.14 with no splicing effect.

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.1062G>T	p.Thr354Thr	synonymous	Exon 4 of 4	NP_005895.1	O15105-1
	SMAD7	NM_001190821.2		c.1059G>T	p.Thr353Thr	synonymous	Exon 4 of 4	NP_001177750.1	O15105-3
	SMAD7	NM_001190823.2		c.498G>T	p.Thr166Thr	synonymous	Exon 2 of 2	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.1062G>T	p.Thr354Thr	synonymous	Exon 4 of 4	ENSP00000262158.2	O15105-1
	SMAD7	ENST00000589634.1	TSL:4	c.1059G>T	p.Thr353Thr	synonymous	Exon 4 of 4	ENSP00000467621.1	O15105-3
	SMAD7	ENST00000911789.1		c.987G>T	p.Thr329Thr	synonymous	Exon 3 of 3	ENSP00000581848.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	8.5
DANN	Benign	0.66
PhyloP100		2.1

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: rs780863704; hg19: chr18-46447961;