4-145515134-CTGTG-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005900.3(SMAD1):c.400+161_400+164del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 530,916 control chromosomes in the GnomAD database, including 69 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (64 hom., cov: 0)
  • Exomes 𝑓: 0.043 (5 hom.)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.377

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 4-145515134-CTGTG-C is Benign according to our data. Variant chr4-145515134-CTGTG-C is described in ClinVar as [Benign]. Clinvar id is 1226228.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD1	NM_005900.3	c.400+161_400+164del		intron_variant		ENST00000302085.9
SMAD1-AS1	NR_126371.1	n.182-148_182-145del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD1	ENST00000302085.9	c.400+161_400+164del		intron_variant		1	NM_005900.3	P1
SMAD1	ENST00000394092.6	c.400+161_400+164del		intron_variant		1		P1
SMAD1-AS1	ENST00000513542.1	n.106-148_106-145del		intron_variant, non_coding_transcript_variant		2
SMAD1	ENST00000515385.1	c.400+161_400+164del		intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3272 AN: 137226 Hom.: 62 Cov.: 0

Gnomad AFR AF: 0.0636

Gnomad AMI AF: 0.0255

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.000916

Gnomad EAS AF: 0.0149

Gnomad SAS AF: 0.0113

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.00699

Gnomad NFE AF: 0.00701

Gnomad OTH AF: 0.0143

GnomAD4 exome AF: 0.0426 AC: 16764 AN: 393598 Hom.: 5 AF XY: 0.0424 AC XY: 8659 AN XY: 204002

Gnomad4 AFR exome AF: 0.0593

Gnomad4 AMR exome AF: 0.0659

Gnomad4 ASJ exome AF: 0.0637

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.0321

Gnomad4 FIN exome AF: 0.0376

Gnomad4 NFE exome AF: 0.0347

Gnomad4 OTH exome AF: 0.0509

GnomAD4 genome AF: 0.0240 AC: 3296 AN: 137318 Hom.: 64 Cov.: 0 AF XY: 0.0242 AC XY: 1599 AN XY: 66026

Gnomad4 AFR AF: 0.0640

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.000916

Gnomad4 EAS AF: 0.0152

Gnomad4 SAS AF: 0.0111

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.00701

Gnomad4 OTH AF: 0.0142

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

May 24, 2021

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Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs377610507; hg19: chr4-146436286;