chr18-48949943-T-C

Position:

• chr18-48949943-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005904.4(SMAD7):​c.482A>G​(p.Lys161Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD7 NM_005904.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30222797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD7	NM_005904.4	c.482A>G	p.Lys161Arg	missense_variant	1/4	ENST00000262158.8
SMAD7	NM_001190821.2	c.482A>G	p.Lys161Arg	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD7	ENST00000262158.8	c.482A>G	p.Lys161Arg	missense_variant	1/4	1	NM_005904.4	P4
SMAD7	ENST00000589634.1	c.482A>G	p.Lys161Arg	missense_variant	1/4	4		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.482A>G (p.K161R) alteration is located in exon 1 (coding exon 1) of the SMAD7 gene. This alteration results from a A to G substitution at nucleotide position 482, causing the lysine (K) at amino acid position 161 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.075	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.60	N;.
REVEL	Uncertain	0.31
Sift	Benign	0.63	T;.
Sift4G	Benign	0.54	T;T
Polyphen		0.0080	B;.
Vest4		0.42
MutPred		0.60		Loss of methylation at K161 (P = 0.0015);Loss of methylation at K161 (P = 0.0015);
MVP		0.94
MPC		0.89
ClinPred		0.72	D
GERP RS		4.7
Varity_R		0.40
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-46476313;