4-145540382-C-T

Variant names:

• chr4-145540382-C-T
• rs3756021
• NM_005900.3:c.658+321C>T

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.658+321C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 152,200 control chromosomes in the GnomAD database, including 4,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.17 (4873 hom., cov: 33)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.285

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=-0.9).
• BP6: Variant 4-145540382-C-T is Benign according to our data. Variant chr4-145540382-C-T is described in ClinVar as [Benign]. Clinvar id is 1229336.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.658+321C>T		intron_variant	Intron 3 of 6	ENST00000302085.9	NP_005891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD1	ENST00000302085.9	c.658+321C>T		intron_variant	Intron 3 of 6	1	NM_005900.3	ENSP00000305769.4
SMAD1	ENST00000394092.6	c.658+321C>T		intron_variant	Intron 3 of 6	1		ENSP00000377652.2
SMAD1	ENST00000515385.1	c.658+321C>T		intron_variant	Intron 3 of 6	2		ENSP00000426568.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25905 AN: 152082 Hom.: 4841 Cov.: 33

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0353

Gnomad OTH AF: 0.153

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

GnomAD4 genome AF: 0.171 AC: 25990 AN: 152200 Hom.: 4873 Cov.: 33 AF XY: 0.170 AC XY: 12663 AN XY: 74408

Gnomad4 AFR AF: 0.459

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.0352

Gnomad4 OTH AF: 0.153

Alfa AF: 0.0584 Hom.: 1225

Bravo AF: 0.190

Asia WGS AF: 0.204 AC: 712 AN: 3478

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	-0.90
CADD	Benign	2.9
DANN	Benign	0.66

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: rs3756021; hg19: chr4-146461534;