Genetic Variant SMAD1:c.-481A>G (chr4-145481440-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.345

Publications

12 publications found

Variant links:

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 links:

SMAD1-AS2 (HGNC:49381): (SMAD1 antisense RNA 2)

SMAD1-AS2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001354812.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354812.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
SMAD1	NM_001354812.1	c.-177+40A>G	intron	N/A	NP_001341741.1	Q15797-1
SMAD1	NM_001354813.1	c.-489A>G	upstream_gene	N/A	NP_001341742.1	Q15797-1
SMAD1	NM_001354814.1	c.-481A>G	upstream_gene	N/A	NP_001341743.1	Q15797-1

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
SMAD1	ENST00000885681.1	c.-481A>G	5_prime_UTR	Exon 1 of 7	ENSP00000555740.1
SMAD1	ENST00000885680.1	c.-177+598A>G	intron	N/A	ENSP00000555739.1
SMAD1	ENST00000885682.1	c.-177+349A>G	intron	N/A	ENSP00000555741.1

Frequencies

GnomAD3 genomes

AF:

0.207

AC:

31415

AN:

152002

Hom.:

4714

Cov.:

show subpopulations

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:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.167

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0714

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.207

AC:

31505

AN:

152120

Hom.:

4750

Cov.:

AF XY:

0.206

AC XY:

15348

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.430

AC:

17830

AN:

41450

American (AMR)

AF:

0.130

AC:

1986

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

439

AN:

3470

East Asian (EAS)

AF:

0.104

AC:

538

AN:

5182

South Asian (SAS)

AF:

0.236

AC:

1137

AN:

4808

European-Finnish (FIN)

AF:

0.113

AC:

1199

AN:

10612

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.114

AC:

7762

AN:

67996

Other (OTH)

AF:

0.177

AC:

374

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1094

2188

3283

4377

5471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

318

636

954

1272

1590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.143

Hom.:

8987

Bravo

AF:

0.217

Asia WGS

AF:

0.224

AC:

778

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

7.8

(source)

DANN

Benign

0.69

PhyloP100

-0.34

PromoterAI

-0.013

Neutral

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over