rs3736242

Variant names:

• chr18-48948376-C-A
• rs3736242
• NM_005904.4:c.667+8G>T

Your query was ambiguous. Multiple possible variants found:

• chr18-48948376-C-A
• chr18-48948376-C-G
• chr18-48948376-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005904.4(SMAD7):​c.667+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SMAD7 NM_005904.4 splice_region, intron
• Scores: Splicing: ADA: 0.01353
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD7	NM_005904.4	c.667+8G>T		splice_region_variant, intron_variant	Intron 2 of 3	ENST00000262158.8	NP_005895.1
SMAD7	NM_001190821.2	c.667+8G>T		splice_region_variant, intron_variant	Intron 2 of 3		NP_001177750.1
SMAD7	NM_001190822.2	c.22+8G>T		splice_region_variant, intron_variant	Intron 2 of 3		NP_001177751.1
SMAD7	XM_047437509.1	c.22+8G>T		splice_region_variant, 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+8G>T		splice_region_variant, intron_variant	Intron 2 of 3	1	NM_005904.4	ENSP00000262158.2
SMAD7	ENST00000589634.1	c.667+8G>T		splice_region_variant, intron_variant	Intron 2 of 3	4		ENSP00000467621.1
SMAD7	ENST00000591805.5	c.22+8G>T		splice_region_variant, intron_variant	Intron 2 of 3	2		ENSP00000466902.1
SMAD7	ENST00000586093.1	c.22+8G>T		splice_region_variant, intron_variant	Intron 1 of 2	2		ENSP00000465590.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422088 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 708928

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000315 AC: 1 AN: 31770

American (AMR) AF: 0.00 AC: 0 AN: 41754

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 38616

South Asian (SAS) AF: 0.00 AC: 0 AN: 82420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083780

Other (OTH) AF: 0.00 AC: 0 AN: 59002

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		1.1
PromoterAI		0.012	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.044
SpliceAI score (max)		0.030		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: rs3736242; hg19: chr18-46474746;