4-145553690-C-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.998-94C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00963 in 1,139,894 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (186 hom., cov: 31)
  • Exomes 𝑓: 0.0067 (162 hom.)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0320

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=-0.88).
• BP6: Variant 4-145553690-C-T is Benign according to our data. Variant chr4-145553690-C-T is described in ClinVar as [Benign]. Clinvar id is 1282393.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD1	NM_005900.3	c.998-94C>T		intron_variant		ENST00000302085.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD1	ENST00000302085.9	c.998-94C>T		intron_variant		1	NM_005900.3	P1

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4339 AN: 152102 Hom.: 186 Cov.: 31

Gnomad AFR AF: 0.0835

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.0505

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.0186

GnomAD4 exome AF: 0.00671 AC: 6626 AN: 987674 Hom.: 162 AF XY: 0.00647 AC XY: 3265 AN XY: 504294

Gnomad4 AFR exome AF: 0.0841

Gnomad4 AMR exome AF: 0.0268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0405

Gnomad4 SAS exome AF: 0.0112

Gnomad4 FIN exome AF: 0.000124

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.0286 AC: 4350 AN: 152220 Hom.: 186 Cov.: 31 AF XY: 0.0280 AC XY: 2085 AN XY: 74418

Gnomad4 AFR AF: 0.0835

Gnomad4 AMR AF: 0.0264

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.0506

Gnomad4 SAS AF: 0.00995

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.00243 Hom.: 2

Bravo AF: 0.0341

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

May 21, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	7.1
Dann	Benign	0.56

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: rs73852353; hg19: chr4-146474842;