4-145515134-C-CTGTGTG

Position:

• chr4-145515134-C-CTGTGTG

Variant summary

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

The NM_005900.3(SMAD1):​c.400+159_400+164dupGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 534,280 control chromosomes in the GnomAD database, including 187 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.052 (180 hom., cov: 0)
  • Exomes 𝑓: 0.021 (7 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-C-CTGTGTG is Benign according to our data. Variant chr4-145515134-C-CTGTGTG is described in ClinVar as [Benign]. Clinvar id is 1260409.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.400+159_400+164dupGTGTGT		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+121_400+122insTGTGTG		intron_variant		1	NM_005900.3	ENSP00000305769.4
SMAD1	ENST00000394092.6	c.400+121_400+122insTGTGTG		intron_variant		1		ENSP00000377652.2
SMAD1	ENST00000515385.1	c.400+121_400+122insTGTGTG		intron_variant		2		ENSP00000426568.1
SMAD1-AS1	ENST00000513542.1	n.106-145_106-144insCACACA		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0523 AC: 7171 AN: 137188 Hom.: 181 Cov.: 0

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.0814

Gnomad AMR AF: 0.0392

Gnomad ASJ AF: 0.0275

Gnomad EAS AF: 0.0353

Gnomad SAS AF: 0.0403

Gnomad FIN AF: 0.0469

Gnomad MID AF: 0.0521

Gnomad NFE AF: 0.0597

Gnomad OTH AF: 0.0535

GnomAD4 exome AF: 0.0211 AC: 8393 AN: 397000 Hom.: 7 AF XY: 0.0210 AC XY: 4313 AN XY: 205656

Gnomad4 AFR exome AF: 0.0204

Gnomad4 AMR exome AF: 0.0131

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.0284

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.0257

Gnomad4 NFE exome AF: 0.0215

Gnomad4 OTH exome AF: 0.0229

GnomAD4 genome AF: 0.0523 AC: 7180 AN: 137280 Hom.: 180 Cov.: 0 AF XY: 0.0490 AC XY: 3238 AN XY: 66016

Gnomad4 AFR AF: 0.0504

Gnomad4 AMR AF: 0.0392

Gnomad4 ASJ AF: 0.0275

Gnomad4 EAS AF: 0.0354

Gnomad4 SAS AF: 0.0410

Gnomad4 FIN AF: 0.0469

Gnomad4 NFE AF: 0.0597

Gnomad4 OTH AF: 0.0530

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 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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;