chr4-145507232-A-G

Variant names:

• chr4-145507232-A-G
• rs2118438
• NM_005900.3:c.-176-7206A>G

Variant summary

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

The NM_005900.3(SMAD1):​c.-176-7206A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 151,224 control chromosomes in the GnomAD database, including 51,626 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 0.82 (51626 hom., cov: 29)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.19

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=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.-176-7206A>G		intron_variant	Intron 1 of 6	ENST00000302085.9	NP_005891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD1	ENST00000302085.9	c.-176-7206A>G		intron_variant	Intron 1 of 6	1	NM_005900.3	ENSP00000305769.4

Frequencies

GnomAD3 genomes AF: 0.818 AC: 123649 AN: 151112 Hom.: 51579 Cov.: 29

Gnomad AFR AF: 0.956

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.801

Gnomad FIN AF: 0.799

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.789

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

GnomAD4 genome AF: 0.818 AC: 123744 AN: 151224 Hom.: 51626 Cov.: 29 AF XY: 0.811 AC XY: 59964 AN XY: 73916

Gnomad4 AFR AF: 0.956

Gnomad4 AMR AF: 0.669

Gnomad4 ASJ AF: 0.767

Gnomad4 EAS AF: 0.462

Gnomad4 SAS AF: 0.801

Gnomad4 FIN AF: 0.799

Gnomad4 NFE AF: 0.804

Gnomad4 OTH AF: 0.788

Alfa AF: 0.784 Hom.: 3473

Bravo AF: 0.809

Asia WGS AF: 0.665 AC: 2301 AN: 3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.060
DANN	Benign	0.25

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: rs2118438; hg19: chr4-146428384;