rs3756021

Variant names:

• chr4-145540382-C-T
• rs3756021
• NM_005900.3:c.658+321C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005900.3(SMAD1):​c.658+321C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 152,200 control chromosomes in the GnomAD database, including 4,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.17 (4873 hom., cov: 33)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.285
• Publications: 3 publications found

Genes affected

SMAD1 (HGNC:6767): (SMAD family member 1) The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein mediates the signals of the bone morphogenetic proteins (BMPs), which are involved in a range of biological activities including cell growth, apoptosis, morphogenesis, development and immune responses. In response to BMP ligands, this protein can be phosphorylated and activated by the BMP receptor kinase. The phosphorylated form of this protein forms a complex with SMAD4, which is important for its function in the transcription regulation. This protein is a target for SMAD-specific E3 ubiquitin ligases, such as SMURF1 and SMURF2, and undergoes ubiquitination and proteasome-mediated degradation. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]

SMAD1 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-145540382-C-T is Benign according to our data. Variant chr4-145540382-C-T is described in ClinVar as Benign. ClinVar VariationId is 1229336.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005900.3. 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
	SMAD1	NM_005900.3	MANE Select	c.658+321C>T		intron	N/A	NP_005891.1	Q15797-1
	SMAD1	NM_001003688.1		c.658+321C>T		intron	N/A	NP_001003688.1	Q15797-1
	SMAD1	NM_001354811.1		c.658+321C>T		intron	N/A	NP_001341740.1	Q15797-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD1	ENST00000302085.9	TSL:1 MANE Select	c.658+321C>T		intron	N/A	ENSP00000305769.4	Q15797-1
	SMAD1	ENST00000394092.6	TSL:1	c.658+321C>T		intron	N/A	ENSP00000377652.2	Q15797-1
	SMAD1	ENST00000515385.1	TSL:2	c.658+321C>T		intron	N/A	ENSP00000426568.1	Q15797-1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25905 AN: 152082 Hom.: 4841 Cov.: 33

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0353

Gnomad OTH AF: 0.153

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.171 AC: 25990 AN: 152200 Hom.: 4873 Cov.: 33 AF XY: 0.170 AC XY: 12663 AN XY: 74408

African (AFR) AF: 0.459 AC: 19035 AN: 41504

American (AMR) AF: 0.133 AC: 2034 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 350 AN: 3464

East Asian (EAS) AF: 0.142 AC: 739 AN: 5186

South Asian (SAS) AF: 0.178 AC: 857 AN: 4816

European-Finnish (FIN) AF: 0.0195 AC: 207 AN: 10602

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0352 AC: 2397 AN: 68010

Other (OTH) AF: 0.153 AC: 324 AN: 2116

Alfa AF: 0.0784 Hom.: 5536

Bravo AF: 0.190

Asia WGS AF: 0.204 AC: 712 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.9
DANN	Benign	0.66
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs3756021; hg19: chr4-146461534;