rs6537355

Positions:

• chr4-145481440-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354812.1(SMAD1):​c.-177+40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,142 control chromosomes in the GnomAD database, including 4,750 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (4750 hom., cov: 31)
  • Exomes 𝑓: 0.091 (0 hom.)
• Consequence: SMAD1 NM_001354812.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.345

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD1	NM_001354812.1	c.-177+40A>G		intron_variant			NP_001341741.1
SMAD1	XM_047415690.1	c.-177+598A>G		intron_variant			XP_047271646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD1	ENST00000514778.1	c.-177+126A>G		intron_variant		4		ENSP00000424959.1
SMAD1	ENST00000507594.1	c.-177+40A>G		intron_variant		4		ENSP00000424649.1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31415 AN: 152002 Hom.: 4714 Cov.: 31

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.176

GnomAD4 exome AF: 0.0909 AC: 2 AN: 22 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.0714

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.207 AC: 31505 AN: 152120 Hom.: 4750 Cov.: 31 AF XY: 0.206 AC XY: 15348 AN XY: 74390

Gnomad4 AFR AF: 0.430

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.177

Alfa AF: 0.131 Hom.: 3301

Bravo AF: 0.217

Asia WGS AF: 0.224 AC: 778 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.8
DANN	Benign	0.69

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6537355; hg19: chr4-146402592;