rs714195

Variant names:

• chr4-145524528-T-C
• rs714195
• NM_005900.3:c.400+9515T>C

Variant summary

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

The NM_005900.3(SMAD1):​c.400+9515T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 152,046 control chromosomes in the GnomAD database, including 27,166 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 0.59 (27166 hom., cov: 32)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.400+9515T>C		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.400+9515T>C		intron_variant	Intron 2 of 6	1	NM_005900.3	ENSP00000305769.4
SMAD1	ENST00000394092.6	c.400+9515T>C		intron_variant	Intron 2 of 6	1		ENSP00000377652.2
SMAD1	ENST00000515385.1	c.400+9515T>C		intron_variant	Intron 2 of 6	2		ENSP00000426568.1

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89169 AN: 151930 Hom.: 27116 Cov.: 32

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.552

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

GnomAD4 genome AF: 0.587 AC: 89275 AN: 152046 Hom.: 27166 Cov.: 32 AF XY: 0.581 AC XY: 43210 AN XY: 74318

African (AFR) AF: 0.726 AC: 30110 AN: 41490

American (AMR) AF: 0.453 AC: 6926 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1576 AN: 3470

East Asian (EAS) AF: 0.273 AC: 1411 AN: 5176

South Asian (SAS) AF: 0.577 AC: 2780 AN: 4814

European-Finnish (FIN) AF: 0.561 AC: 5910 AN: 10528

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.571 AC: 38791 AN: 67970

Other (OTH) AF: 0.553 AC: 1170 AN: 2116

Alfa AF: 0.582 Hom.: 3774

Bravo AF: 0.580

Asia WGS AF: 0.480 AC: 1669 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.5
DANN	Benign	0.77
PhyloP100		0.034
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: rs714195; hg19: chr4-146445680;