4-145542594-C-T

Variant names:

• chr4-145542594-C-T
• rs1048829612
• NM_005900.3:c.671C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP3 BS2

The NM_005900.3(SMAD1):​c.671C>T​(p.Pro224Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,455,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SMAD1 NM_005900.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen, PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005900.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD1	NM_005900.3	MANE Select	c.671C>T	p.Pro224Leu	missense	Exon 4 of 7	NP_005891.1	Q15797-1
	SMAD1	NM_001003688.1		c.671C>T	p.Pro224Leu	missense	Exon 4 of 7	NP_001003688.1	Q15797-1
	SMAD1	NM_001354811.1		c.671C>T	p.Pro224Leu	missense	Exon 4 of 7	NP_001341740.1	Q15797-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD1	ENST00000302085.9	TSL:1 MANE Select	c.671C>T	p.Pro224Leu	missense	Exon 4 of 7	ENSP00000305769.4	Q15797-1
	SMAD1	ENST00000394092.6	TSL:1	c.671C>T	p.Pro224Leu	missense	Exon 4 of 7	ENSP00000377652.2	Q15797-1
	SMAD1	ENST00000515385.1	TSL:2	c.671C>T	p.Pro224Leu	missense	Exon 4 of 7	ENSP00000426568.1	Q15797-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1455216 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 723866

African (AFR) AF: 0.00 AC: 0 AN: 33172

American (AMR) AF: 0.00 AC: 0 AN: 43496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39266

South Asian (SAS) AF: 0.00 AC: 0 AN: 84782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1109160

Other (OTH) AF: 0.00 AC: 0 AN: 60158

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.060	T
Polyphen		0.92	P
Vest4		0.69
MutPred		0.35		Loss of glycosylation at P224 (P = 0.0113)
MVP		0.79
MPC		0.10
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.57
gMVP		0.53
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1048829612; hg19: chr4-146463746;