4-145515134-CTG-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005900.3(SMAD1):c.400+163_400+164del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 530,598 control chromosomes in the GnomAD database, including 2,906 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (2589 hom., cov: 0)
  • Exomes 𝑓: 0.16 (317 hom.)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0210

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 -10 ACMG points.

• BP6: Variant 4-145515134-CTG-C is Benign according to our data. Variant chr4-145515134-CTG-C is described in ClinVar as [Benign]. Clinvar id is 1240959.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD1	NM_005900.3	c.400+163_400+164del		intron_variant		ENST00000302085.9
SMAD1-AS1	NR_126371.1	n.182-146_182-145del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD1	ENST00000302085.9	c.400+163_400+164del		intron_variant		1	NM_005900.3	P1
SMAD1	ENST00000394092.6	c.400+163_400+164del		intron_variant		1		P1
SMAD1-AS1	ENST00000513542.1	n.106-146_106-145del		intron_variant, non_coding_transcript_variant		2
SMAD1	ENST00000515385.1	c.400+163_400+164del		intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 27353 AN: 136984 Hom.: 2586 Cov.: 0

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.393

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.262

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.156 AC: 61261 AN: 393522 Hom.: 317 AF XY: 0.156 AC XY: 31731 AN XY: 203932

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.241

Gnomad4 EAS exome AF: 0.301

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.184

GnomAD4 genome AF: 0.200 AC: 27372 AN: 137076 Hom.: 2589 Cov.: 0 AF XY: 0.201 AC XY: 13278 AN XY: 65914

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.325

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.394

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.241

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

Oct 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

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: rs377610507; hg19: chr4-146436286;