rs7698944

Positions:

• chr4-145515199-A-G

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.400+186A>G		intron_variant		ENST00000302085.9	NP_005891.1
SMAD1-AS1	NR_126371.1	n.182-209T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD1	ENST00000302085.9	c.400+186A>G		intron_variant		1	NM_005900.3	ENSP00000305769	P1
SMAD1	ENST00000394092.6	c.400+186A>G		intron_variant		1		ENSP00000377652	P1
SMAD1-AS1	ENST00000513542.1	n.106-209T>C		intron_variant, non_coding_transcript_variant		2
SMAD1	ENST00000515385.1	c.400+186A>G		intron_variant		2		ENSP00000426568	P1

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

Gnomad4 AFR AF: 0.514

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.0773

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.0353

Gnomad4 OTH AF: 0.167

Alfa AF: 0.0732 Hom.: 726

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 12, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.45
DANN	Benign	0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs7698944; hg19: chr4-146436351;