rs714195

Positions:

• chr4-145524528-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.400+9515T>C		intron_variant		ENST00000302085.9	NP_005891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD1	ENST00000302085.9	c.400+9515T>C		intron_variant		1	NM_005900.3	ENSP00000305769.4
SMAD1	ENST00000394092.6	c.400+9515T>C		intron_variant		1		ENSP00000377652.2
SMAD1	ENST00000515385.1	c.400+9515T>C		intron_variant		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

Gnomad4 AFR AF: 0.726

Gnomad4 AMR AF: 0.453

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.273

Gnomad4 SAS AF: 0.577

Gnomad4 FIN AF: 0.561

Gnomad4 NFE AF: 0.571

Gnomad4 OTH AF: 0.553

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

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: rs714195; hg19: chr4-146445680;