rs1065080

Variant names:

• chr15-67164997-A-G
• rs1065080
• ENST00000540846.6:c.-7A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-67164997-A-G
• chr15-67164997-A-T
• chr15-67164997-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001145102.2(SMAD3):​c.-7A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 1,614,074 control chromosomes in the GnomAD database, including 618,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57780 hom., cov: 34)
  • Exomes 𝑓: 0.88 (560371 hom.)
• Consequence: SMAD3 NM_001145102.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 1.30
• Publications: 52 publications found

Genes affected

SMAD3 (HGNC:6769): (SMAD family member 3) The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3. [provided by RefSeq, May 2022]

SMAD3 Gene-Disease associations (from GenCC):

• aneurysm-osteoarthritis syndrome

  Inheritance: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2951502E-6).
• BP6: Variant 15-67164997-A-G is Benign according to our data. Variant chr15-67164997-A-G is described in ClinVar as Benign. ClinVar VariationId is 139217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145102.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.309A>G	p.Leu103Leu	synonymous	Exon 2 of 9	NP_005893.1	P84022-1
	SMAD3	NM_001145102.2		c.-7A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001138574.1	P84022-3
	SMAD3	NM_001407016.1		c.-7A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001393945.1	P84022-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000540846.6	TSL:1	c.-7A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	ENSP00000437757.2	P84022-3
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.309A>G	p.Leu103Leu	synonymous	Exon 2 of 9	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000439724.7	TSL:1	c.177A>G	p.Leu59Leu	synonymous	Exon 2 of 9	ENSP00000401133.3	P84022-2

Frequencies

GnomAD3 genomes AF: 0.871 AC: 132490 AN: 152198 Hom.: 57735 Cov.: 34

Gnomad AFR AF: 0.862

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.910

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.793

Gnomad FIN AF: 0.863

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.882

Gnomad OTH AF: 0.883

GnomAD2 exomes AF: 0.867 AC: 217954 AN: 251434 AF XY: 0.862

Gnomad AFR exome AF: 0.866

Gnomad AMR exome AF: 0.944

Gnomad ASJ exome AF: 0.845

Gnomad EAS exome AF: 0.754

Gnomad FIN exome AF: 0.867

Gnomad NFE exome AF: 0.882

Gnomad OTH exome AF: 0.871

GnomAD4 exome AF: 0.875 AC: 1279048 AN: 1461758 Hom.: 560371 Cov.: 64 AF XY: 0.873 AC XY: 634533 AN XY: 727186

African (AFR) AF: 0.865 AC: 28946 AN: 33480

American (AMR) AF: 0.940 AC: 42048 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.848 AC: 22166 AN: 26136

East Asian (EAS) AF: 0.808 AC: 32063 AN: 39696

South Asian (SAS) AF: 0.804 AC: 69347 AN: 86254

European-Finnish (FIN) AF: 0.861 AC: 45962 AN: 53388

Middle Eastern (MID) AF: 0.867 AC: 4962 AN: 5720

European-Non Finnish (NFE) AF: 0.883 AC: 981347 AN: 1111982

Other (OTH) AF: 0.865 AC: 52207 AN: 60378

GnomAD4 genome AF: 0.870 AC: 132591 AN: 152316 Hom.: 57780 Cov.: 34 AF XY: 0.869 AC XY: 64729 AN XY: 74480

African (AFR) AF: 0.862 AC: 35834 AN: 41568

American (AMR) AF: 0.910 AC: 13927 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2916 AN: 3472

East Asian (EAS) AF: 0.772 AC: 3995 AN: 5172

South Asian (SAS) AF: 0.794 AC: 3830 AN: 4826

European-Finnish (FIN) AF: 0.863 AC: 9166 AN: 10622

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.882 AC: 59982 AN: 68026

Other (OTH) AF: 0.884 AC: 1871 AN: 2116

Alfa AF: 0.879 Hom.: 161296

Bravo AF: 0.878

TwinsUK AF: 0.884 AC: 3278

ALSPAC AF: 0.888 AC: 3424

ESP6500AA AF: 0.873 AC: 3842

ESP6500EA AF: 0.884 AC: 7598

ExAC AF: 0.863 AC: 104820

Asia WGS AF: 0.782 AC: 2723 AN: 3478

EpiCase AF: 0.886

EpiControl AF: 0.887

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	5	Aneurysm-osteoarthritis syndrome (5)
-	-	5	Familial thoracic aortic aneurysm and aortic dissection (5)
-	-	1	not provided (1)
-	-	1	Thoracic aortic aneurysm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.0
DANN	Benign	0.96
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0000013	T
PhyloP100		1.3
PROVEAN	Pathogenic	-9.0	D
Vest4		0.12
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1065080; hg19: chr15-67457335; COSMIC: COSV59284976; COSMIC: COSV59284976;