rs1016792

Variant names:

• chr4-145557627-C-T
• rs1016792
• NM_005900.3:c.1255-164C>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.1255-164C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 152,088 control chromosomes in the GnomAD database, including 51,198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.81 (51198 hom., cov: 30)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.44
• Publications: 8 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-145557627-C-T is Benign according to our data. Variant chr4-145557627-C-T is described in ClinVar as Benign. ClinVar VariationId is 1227457.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.1255-164C>T		intron_variant	Intron 6 of 6	ENST00000302085.9	NP_005891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD1	ENST00000302085.9	c.1255-164C>T		intron_variant	Intron 6 of 6	1	NM_005900.3	ENSP00000305769.4
SMAD1	ENST00000394092.6	c.1255-164C>T		intron_variant	Intron 6 of 6	1		ENSP00000377652.2
SMAD1	ENST00000515385.1	c.1255-164C>T		intron_variant	Intron 6 of 6	2		ENSP00000426568.1
SMAD1	ENST00000511125.1	n.3005-164C>T		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.813 AC: 123586 AN: 151970 Hom.: 51147 Cov.: 30

Gnomad AFR AF: 0.956

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.785

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

GnomAD4 genome AF: 0.813 AC: 123685 AN: 152088 Hom.: 51198 Cov.: 30 AF XY: 0.805 AC XY: 59804 AN XY: 74300

African (AFR) AF: 0.956 AC: 39682 AN: 41514

American (AMR) AF: 0.636 AC: 9720 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 2636 AN: 3470

East Asian (EAS) AF: 0.615 AC: 3166 AN: 5146

South Asian (SAS) AF: 0.763 AC: 3674 AN: 4818

European-Finnish (FIN) AF: 0.752 AC: 7923 AN: 10542

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.800 AC: 54395 AN: 68000

Other (OTH) AF: 0.783 AC: 1653 AN: 2110

Alfa AF: 0.793 Hom.: 89918

Bravo AF: 0.809

Asia WGS AF: 0.695 AC: 2420 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.75
DANN	Benign	0.70
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1016792; hg19: chr4-146478779;