4-145515134-CTGTGTGTG-C

Position:

• chr4-145515134-CTGTGTGTG-C

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+157_400+164delGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00886 in 535,442 control chromosomes in the GnomAD database, including 49 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (45 hom., cov: 0)
  • Exomes 𝑓: 0.0057 (4 hom.)
• Consequence: SMAD1 NM_005900.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.48

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-CTGTGTGTG-C is Benign according to our data. Variant chr4-145515134-CTGTGTGTG-C is described in ClinVar as [Benign]. Clinvar id is 1269214.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0179 (2460/137390) while in subpopulation AFR AF= 0.0461 (1684/36568). AF 95% confidence interval is 0.0442. There are 45 homozygotes in gnomad4. There are 1333 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2460 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD1	NM_005900.3	c.400+157_400+164delGTGTGTGT		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+122_400+129delTGTGTGTG		intron_variant		1	NM_005900.3	ENSP00000305769.4
SMAD1	ENST00000394092.6	c.400+122_400+129delTGTGTGTG		intron_variant		1		ENSP00000377652.2
SMAD1	ENST00000515385.1	c.400+122_400+129delTGTGTGTG		intron_variant		2		ENSP00000426568.1
SMAD1-AS1	ENST00000513542.1	n.106-152_106-145delCACACACA		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2449 AN: 137298 Hom.: 44 Cov.: 0

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00978

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00255

Gnomad SAS AF: 0.00706

Gnomad FIN AF: 0.0534

Gnomad MID AF: 0.00694

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.0143

GnomAD4 exome AF: 0.00574 AC: 2284 AN: 398052 Hom.: 4 AF XY: 0.00551 AC XY: 1136 AN XY: 206208

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.00875

Gnomad4 ASJ exome AF: 0.00188

Gnomad4 EAS exome AF: 0.00391

Gnomad4 SAS exome AF: 0.00464

Gnomad4 FIN exome AF: 0.0388

Gnomad4 NFE exome AF: 0.00171

Gnomad4 OTH exome AF: 0.00651

GnomAD4 genome AF: 0.0179 AC: 2460 AN: 137390 Hom.: 45 Cov.: 0 AF XY: 0.0202 AC XY: 1333 AN XY: 66074

Gnomad4 AFR AF: 0.0461

Gnomad4 AMR AF: 0.00984

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00256

Gnomad4 SAS AF: 0.00708

Gnomad4 FIN AF: 0.0534

Gnomad4 NFE AF: 0.00190

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 20, 2021

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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: rs377610507; hg19: chr4-146436286;