rs587777018

Positions:

• chr4-145514621-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_005900.3(SMAD1):​c.8T>C​(p.Val3Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,449,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMAD1 NM_005900.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: 6.02

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMAD1. . Gene score misZ 2.2809 (greater than the threshold 3.09). Trascript score misZ 3.4386 (greater than threshold 3.09). GenCC has associacion of gene with pulmonary arterial hypertension.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.8T>C	p.Val3Ala	missense_variant	2/7	ENST00000302085.9	NP_005891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD1	ENST00000302085.9	c.8T>C	p.Val3Ala	missense_variant	2/7	1	NM_005900.3	ENSP00000305769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449996 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

Variant of unknown significance Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Dec 01, 2011

- -

Pulmonary hypertension, primary, 1 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Rare Disease Genomics Group, St George's University of London

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;T;D;.;T;.;D;D
Eigen	Benign	-0.12
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D;.;D;D;.;.;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.2	.;.;.;L;.;.;.;L;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.9	N;N;N;N;N;N;D;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D;D;D;D;D;D;.;D;D
Sift4G	Benign	0.089	T;D;T;T;T;D;.;T;T
Polyphen		0.0070, 0.0040	.;.;.;B;B;.;.;B;B
Vest4		0.79, 0.67, 0.80
MutPred		0.21		Gain of disorder (P = 0.0954);Gain of disorder (P = 0.0954);Gain of disorder (P = 0.0954);Gain of disorder (P = 0.0954);Gain of disorder (P = 0.0954);Gain of disorder (P = 0.0954);Gain of disorder (P = 0.0954);Gain of disorder (P = 0.0954);Gain of disorder (P = 0.0954);
MVP		0.99
MPC		1.7
ClinPred		0.84	D
GERP RS		5.0
Varity_R		0.31
gMVP		0.53

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: rs587777018; hg19: chr4-146435773;