18-48948445-T-G

Variant names:

• chr18-48948445-T-G
• NM_005904.4:c.614-8A>C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_005904.4(SMAD7):​c.614-8A>C variant causes a splice region, intron 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMAD7 NM_005904.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005180
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.59

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 18-48948445-T-G is Benign according to our data. Variant chr18-48948445-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3350989.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD7	NM_005904.4	c.614-8A>C		splice_region_variant, intron_variant	Intron 1 of 3	ENST00000262158.8	NP_005895.1
SMAD7	NM_001190821.2	c.614-8A>C		splice_region_variant, intron_variant	Intron 1 of 3		NP_001177750.1
SMAD7	NM_001190822.2	c.-32-8A>C		splice_region_variant, intron_variant	Intron 1 of 3		NP_001177751.1
SMAD7	XM_047437509.1	c.-32-8A>C		splice_region_variant, intron_variant	Intron 1 of 3		XP_047293465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD7	ENST00000262158.8	c.614-8A>C		splice_region_variant, intron_variant	Intron 1 of 3	1	NM_005904.4	ENSP00000262158.2
SMAD7	ENST00000586093.1	c.-40A>C		5_prime_UTR_variant	Exon 1 of 3	2		ENSP00000465590.1
SMAD7	ENST00000589634.1	c.614-8A>C		splice_region_variant, intron_variant	Intron 1 of 3	4		ENSP00000467621.1
SMAD7	ENST00000591805.5	c.-32-8A>C		splice_region_variant, intron_variant	Intron 1 of 3	2		ENSP00000466902.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SMAD7-related disorder Benign:1

Jul 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00052
dbscSNV1_RF	Benign	0.016
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-46474815;