4-145542814-T-C

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.775+116T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 645,584 control chromosomes in the GnomAD database, including 98,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (26284 hom., cov: 32)
  • Exomes 𝑓: 0.53 (72510 hom.)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.176

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 4-145542814-T-C is Benign according to our data. Variant chr4-145542814-T-C is described in ClinVar as [Benign]. Clinvar id is 1249634.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD1	NM_005900.3	c.775+116T>C		intron_variant		ENST00000302085.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD1	ENST00000302085.9	c.775+116T>C		intron_variant		1	NM_005900.3	P1
SMAD1	ENST00000394092.6	c.775+116T>C		intron_variant		1		P1
SMAD1	ENST00000515385.1	c.775+116T>C		intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87811 AN: 151908 Hom.: 26238 Cov.: 32

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.543

GnomAD4 exome AF: 0.531 AC: 262205 AN: 493558 Hom.: 72510 AF XY: 0.533 AC XY: 139576 AN XY: 261742

Gnomad4 AFR exome AF: 0.692

Gnomad4 AMR exome AF: 0.382

Gnomad4 ASJ exome AF: 0.440

Gnomad4 EAS exome AF: 0.247

Gnomad4 SAS exome AF: 0.561

Gnomad4 FIN exome AF: 0.554

Gnomad4 NFE exome AF: 0.561

Gnomad4 OTH exome AF: 0.539

GnomAD4 genome AF: 0.578 AC: 87913 AN: 152026 Hom.: 26284 Cov.: 32 AF XY: 0.574 AC XY: 42615 AN XY: 74298

Gnomad4 AFR AF: 0.700

Gnomad4 AMR AF: 0.450

Gnomad4 ASJ AF: 0.448

Gnomad4 EAS AF: 0.274

Gnomad4 SAS AF: 0.576

Gnomad4 FIN AF: 0.564

Gnomad4 NFE AF: 0.567

Gnomad4 OTH AF: 0.543

Alfa AF: 0.507 Hom.: 4965

Bravo AF: 0.570

Asia WGS AF: 0.483 AC: 1682 AN: 3478

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

Sep 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	4.0
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1497126; hg19: chr4-146463966;