chr18-48921479-C-T

Variant names:

• chr18-48921479-C-T
• rs2069859074
• NM_005904.4:c.1174G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005904.4(SMAD7):​c.1174G>A​(p.Gly392Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMAD7 NM_005904.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

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.1174G>A	p.Gly392Ser	missense	Exon 4 of 4	NP_005895.1	O15105-1
	SMAD7	NM_001190821.2		c.1171G>A	p.Gly391Ser	missense	Exon 4 of 4	NP_001177750.1	O15105-3
	SMAD7	NM_001190823.2		c.610G>A	p.Gly204Ser	missense	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.1174G>A	p.Gly392Ser	missense	Exon 4 of 4	ENSP00000262158.2	O15105-1
	SMAD7	ENST00000589634.1	TSL:4	c.1171G>A	p.Gly391Ser	missense	Exon 4 of 4	ENSP00000467621.1	O15105-3
	SMAD7	ENST00000911789.1		c.1099G>A	p.Gly367Ser	missense	Exon 3 of 3	ENSP00000581848.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.2	L
PhyloP100		6.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.86	N
REVEL	Pathogenic	0.69
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		0.89	P
Vest4		0.71
MutPred		0.54		Loss of loop (P = 0.0804)
MVP		0.89
MPC		2.2
ClinPred		0.89	D
GERP RS		5.7
Varity_R		0.19
gMVP		0.72
Mutation Taster		=67/33	polymorphism

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: rs2069859074; hg19: chr18-46447849; COSMIC: COSV50988908; COSMIC: COSV50988908;