rs7698944

Variant names:

• chr4-145515199-A-G
• rs7698944
• NM_005900.3:c.400+186A>G

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.400+186A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 150,814 control chromosomes in the GnomAD database, including 5,891 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.18 (5891 hom., cov: 31)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.352
• Publications: 1 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-AS1 (HGNC:49379): (SMAD1 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 4-145515199-A-G is Benign according to our data. Variant chr4-145515199-A-G is described in ClinVar as Benign. ClinVar VariationId is 1226442.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.400+186A>G		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+186A>G		intron_variant	Intron 2 of 6	1	NM_005900.3	ENSP00000305769.4

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27702 AN: 150694 Hom.: 5853 Cov.: 31

Gnomad AFR AF: 0.513

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0773

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.163

Gnomad NFE AF: 0.0353

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.184 AC: 27793 AN: 150814 Hom.: 5891 Cov.: 31 AF XY: 0.183 AC XY: 13464 AN XY: 73666

African (AFR) AF: 0.514 AC: 20998 AN: 40872

American (AMR) AF: 0.137 AC: 2067 AN: 15134

Ashkenazi Jewish (ASJ) AF: 0.0773 AC: 267 AN: 3452

East Asian (EAS) AF: 0.141 AC: 723 AN: 5122

South Asian (SAS) AF: 0.158 AC: 750 AN: 4750

European-Finnish (FIN) AF: 0.0195 AC: 204 AN: 10464

Middle Eastern (MID) AF: 0.159 AC: 46 AN: 290

European-Non Finnish (NFE) AF: 0.0353 AC: 2388 AN: 67736

Other (OTH) AF: 0.167 AC: 348 AN: 2084

Alfa AF: 0.0753 Hom.: 857

Bravo AF: 0.207

Asia WGS AF: 0.200 AC: 696 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.45
DANN	Benign	0.41
PhyloP100		0.35
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: rs7698944; hg19: chr4-146436351;