chr4-145515170-G-GTGTGTC

Position:

• chr4-145515170-G-GTGTGTC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_005900.3(SMAD1):​c.400+162_400+163insCTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 149,876 control chromosomes in the GnomAD database, including 74 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.027 (74 hom., cov: 30)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.290

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-AS1 (HGNC:49379): (SMAD1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 4-145515170-G-GTGTGTC is Benign according to our data. Variant chr4-145515170-G-GTGTGTC is described in ClinVar as [Likely_benign]. Clinvar id is 1318376.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0271 (4065/149876) while in subpopulation SAS AF= 0.0423 (199/4700). AF 95% confidence interval is 0.0382. There are 74 homozygotes in gnomad4. There are 1961 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4065 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.400+162_400+163insCTGTGT		intron_variant		ENST00000302085.9	NP_005891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD1	ENST00000302085.9	c.400+157_400+158insTGTGTC		intron_variant		1	NM_005900.3	ENSP00000305769.4
SMAD1	ENST00000394092.6	c.400+157_400+158insTGTGTC		intron_variant		1		ENSP00000377652.2
SMAD1	ENST00000515385.1	c.400+157_400+158insTGTGTC		intron_variant		2		ENSP00000426568.1
SMAD1-AS1	ENST00000513542.1	n.106-181_106-180insGACACA		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4062 AN: 149772 Hom.: 74 Cov.: 30

Gnomad AFR AF: 0.00693

Gnomad AMI AF: 0.00661

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.0276

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0395

Gnomad OTH AF: 0.0270

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

GnomAD4 genome AF: 0.0271 AC: 4065 AN: 149876 Hom.: 74 Cov.: 30 AF XY: 0.0268 AC XY: 1961 AN XY: 73114

Gnomad4 AFR AF: 0.00691

Gnomad4 AMR AF: 0.0226

Gnomad4 ASJ AF: 0.0597

Gnomad4 EAS AF: 0.0274

Gnomad4 SAS AF: 0.0423

Gnomad4 FIN AF: 0.0156

Gnomad4 NFE AF: 0.0395

Gnomad4 OTH AF: 0.0291

Alfa AF: 0.0278 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2020

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs781751692; hg19: chr4-146436322;