4-145540284-A-G

Position:

• chr4-145540284-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005900.3(SMAD1):​c.658+223A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 152,362 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.027 (88 hom., cov: 32)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.25

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-145540284-A-G is Benign according to our data. Variant chr4-145540284-A-G is described in ClinVar as [Benign]. Clinvar id is 1283491.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0275 (4187/152362) while in subpopulation NFE AF= 0.0422 (2869/68030). AF 95% confidence interval is 0.0409. There are 88 homozygotes in gnomad4. There are 1968 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4187 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD1	NM_005900.3	c.658+223A>G		intron_variant		ENST00000302085.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD1	ENST00000302085.9	c.658+223A>G		intron_variant		1	NM_005900.3	P1
SMAD1	ENST00000394092.6	c.658+223A>G		intron_variant		1		P1
SMAD1	ENST00000515385.1	c.658+223A>G		intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4188 AN: 152244 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.00719

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0477

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0422

Gnomad OTH AF: 0.0263

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0275 AC: 4187 AN: 152362 Hom.: 88 Cov.: 32 AF XY: 0.0264 AC XY: 1968 AN XY: 74508

Gnomad4 AFR AF: 0.00716

Gnomad4 AMR AF: 0.0189

Gnomad4 ASJ AF: 0.0158

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.0477

Gnomad4 NFE AF: 0.0422

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0328 Hom.: 10

Bravo AF: 0.0239

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 15, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.30
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs34373983; hg19: chr4-146461436;