4-145542596-C-T

Variant names:

• chr4-145542596-C-T
• rs1375990946
• NM_005900.3:c.673C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005900.3(SMAD1):​c.673C>T​(p.Pro225Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,455,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SMAD1 NM_005900.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.673C>T	p.Pro225Ser	missense_variant	Exon 4 of 7	ENST00000302085.9	NP_005891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD1	ENST00000302085.9	c.673C>T	p.Pro225Ser	missense_variant	Exon 4 of 7	1	NM_005900.3	ENSP00000305769.4
SMAD1	ENST00000394092.6	c.673C>T	p.Pro225Ser	missense_variant	Exon 4 of 7	1		ENSP00000377652.2
SMAD1	ENST00000515385.1	c.673C>T	p.Pro225Ser	missense_variant	Exon 4 of 7	2		ENSP00000426568.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 245204 Hom.: 0 AF XY: 0.00000754 AC XY: 1 AN XY: 132642

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1455848 Hom.: 0 Cov.: 29 AF XY: 0.00000690 AC XY: 5 AN XY: 724220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.673C>T (p.P225S) alteration is located in exon 4 (coding exon 3) of the SMAD1 gene. This alteration results from a C to T substitution at nucleotide position 673, causing the proline (P) at amino acid position 225 to be replaced by a serine (S). 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	Uncertain	0.45
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;D;D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.1	M;M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.54
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.16	B;B;B
Vest4		0.51
MutPred		0.33		Gain of phosphorylation at P225 (P = 0.017);Gain of phosphorylation at P225 (P = 0.017);Gain of phosphorylation at P225 (P = 0.017);
MVP		0.75
MPC		0.10
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.50
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1375990946; hg19: chr4-146463748;