rs11100883

Variant names:

• chr4-145529818-G-A
• rs11100883
• NM_005900.3:c.401-9986G>A

Variant summary

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

The NM_005900.3(SMAD1):​c.401-9986G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 152,088 control chromosomes in the GnomAD database, including 10,027 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 0.32 (10027 hom., cov: 32)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• Publications: 10 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.401-9986G>A		intron_variant	Intron 2 of 6	ENST00000302085.9	NP_005891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD1	ENST00000302085.9	c.401-9986G>A		intron_variant	Intron 2 of 6	1	NM_005900.3	ENSP00000305769.4
SMAD1	ENST00000394092.6	c.401-9986G>A		intron_variant	Intron 2 of 6	1		ENSP00000377652.2
SMAD1	ENST00000515385.1	c.401-9986G>A		intron_variant	Intron 2 of 6	2		ENSP00000426568.1
SMAD1	ENST00000502342.1	n.96+4003G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49353 AN: 151966 Hom.: 10024 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.0972

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.322

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

GnomAD4 genome AF: 0.325 AC: 49353 AN: 152088 Hom.: 10027 Cov.: 32 AF XY: 0.320 AC XY: 23791 AN XY: 74312

African (AFR) AF: 0.107 AC: 4446 AN: 41526

American (AMR) AF: 0.262 AC: 4005 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1035 AN: 3472

East Asian (EAS) AF: 0.0964 AC: 499 AN: 5176

South Asian (SAS) AF: 0.336 AC: 1614 AN: 4810

European-Finnish (FIN) AF: 0.478 AC: 5032 AN: 10532

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.465 AC: 31582 AN: 67970

Other (OTH) AF: 0.318 AC: 671 AN: 2108

Alfa AF: 0.402 Hom.: 42508

Bravo AF: 0.296

Asia WGS AF: 0.193 AC: 672 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.26
DANN	Benign	0.76
PhyloP100		-1.5
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: rs11100883; hg19: chr4-146450970;