4-145542675-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.752T>C(p.Leu251Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMAD1 NM_005900.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMAD1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD1	NM_005900.3	c.752T>C	p.Leu251Pro	missense_variant	4/7	ENST00000302085.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD1	ENST00000302085.9	c.752T>C	p.Leu251Pro	missense_variant	4/7	1	NM_005900.3	P1
SMAD1	ENST00000394092.6	c.752T>C	p.Leu251Pro	missense_variant	4/7	1		P1
SMAD1	ENST00000515385.1	c.752T>C	p.Leu251Pro	missense_variant	4/7	2		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.752T>C (p.L251P) alteration is located in exon 4 (coding exon 3) of the SMAD1 gene. This alteration results from a T to C substitution at nucleotide position 752, causing the leucine (L) at amino acid position 251 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T
Eigen	Benign	-0.071
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.73	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.79	N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.57
MutPred		0.47		Gain of glycosylation at L251 (P = 0.005);Gain of glycosylation at L251 (P = 0.005);Gain of glycosylation at L251 (P = 0.005);
MVP		0.68
MPC		0.17
ClinPred		0.64	D
GERP RS		5.6
Varity_R		0.19
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-146463827;