4-145507232-A-G

Variant names:

• chr4-145507232-A-G
• rs2118438
• NM_005900.3:c.-176-7206A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005900.3(SMAD1):​c.-176-7206A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 151,224 control chromosomes in the GnomAD database, including 51,626 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.82 (51626 hom., cov: 29)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.19
• Publications: 6 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):

• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.948 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD1	NM_005900.3	MANE Select	c.-176-7206A>G		intron	N/A	NP_005891.1
	SMAD1	NM_001003688.1		c.-176-7206A>G		intron	N/A	NP_001003688.1
	SMAD1	NM_001354811.1		c.-176-7206A>G		intron	N/A	NP_001341740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD1	ENST00000302085.9	TSL:1 MANE Select	c.-176-7206A>G		intron	N/A	ENSP00000305769.4
	SMAD1	ENST00000394092.6	TSL:1	c.-176-7206A>G		intron	N/A	ENSP00000377652.2
	SMAD1	ENST00000515385.1	TSL:2	c.-176-7206A>G		intron	N/A	ENSP00000426568.1

Frequencies

GnomAD3 genomes AF: 0.818 AC: 123649 AN: 151112 Hom.: 51579 Cov.: 29

Gnomad AFR AF: 0.956

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.801

Gnomad FIN AF: 0.799

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.789

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

GnomAD4 genome AF: 0.818 AC: 123744 AN: 151224 Hom.: 51626 Cov.: 29 AF XY: 0.811 AC XY: 59964 AN XY: 73916

African (AFR) AF: 0.956 AC: 39538 AN: 41356

American (AMR) AF: 0.669 AC: 10194 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 2660 AN: 3466

East Asian (EAS) AF: 0.462 AC: 2384 AN: 5158

South Asian (SAS) AF: 0.801 AC: 3853 AN: 4810

European-Finnish (FIN) AF: 0.799 AC: 8169 AN: 10224

Middle Eastern (MID) AF: 0.760 AC: 222 AN: 292

European-Non Finnish (NFE) AF: 0.804 AC: 54413 AN: 67674

Other (OTH) AF: 0.788 AC: 1653 AN: 2098

Alfa AF: 0.784 Hom.: 3473

Bravo AF: 0.809

Asia WGS AF: 0.665 AC: 2301 AN: 3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.060
DANN	Benign	0.25
PhyloP100		-2.2
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: rs2118438; hg19: chr4-146428384;