chr15-67191641-G-A

Variant names:

• chr15-67191641-G-A
• rs8031440
• NM_005902.4:c.*1105G>A

Variant summary

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

The NM_005902.4(SMAD3):​c.*1105G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 232,796 control chromosomes in the GnomAD database, including 7,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3819 hom., cov: 32)
  • Exomes 𝑓: 0.27 (3355 hom.)
• Consequence: SMAD3 NM_005902.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.93
• Publications: 20 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 (BayesDel_noAF=-0.79).
• BP6: Variant 15-67191641-G-A is Benign according to our data. Variant chr15-67191641-G-A is described in ClinVar as Benign. ClinVar VariationId is 316892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005902.4. 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.*1105G>A		3_prime_UTR	Exon 9 of 9	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.*1105G>A		3_prime_UTR	Exon 10 of 10	NP_001393940.1	H3BQ00
	SMAD3	NM_001145103.2		c.*1105G>A		3_prime_UTR	Exon 9 of 9	NP_001138575.1	P84022-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.*1105G>A		3_prime_UTR	Exon 9 of 9	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000714110.1		c.*1105G>A		3_prime_UTR	Exon 9 of 9	ENSP00000519402.1	A0AAQ5BHK2
	SMAD3	ENST00000714109.1		c.*1105G>A		3_prime_UTR	Exon 8 of 8	ENSP00000519401.1	A0AAQ5BHI7

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30634 AN: 152042 Hom.: 3818 Cov.: 32

Gnomad AFR AF: 0.0741

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.238

GnomAD4 exome AF: 0.267 AC: 21534 AN: 80636 Hom.: 3355 Cov.: 0 AF XY: 0.266 AC XY: 9878 AN XY: 37074

African (AFR) AF: 0.0775 AC: 300 AN: 3870

American (AMR) AF: 0.312 AC: 775 AN: 2484

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1714 AN: 5088

East Asian (EAS) AF: 0.481 AC: 5510 AN: 11462

South Asian (SAS) AF: 0.296 AC: 207 AN: 700

European-Finnish (FIN) AF: 0.155 AC: 9 AN: 58

Middle Eastern (MID) AF: 0.289 AC: 141 AN: 488

European-Non Finnish (NFE) AF: 0.227 AC: 11299 AN: 49742

Other (OTH) AF: 0.234 AC: 1579 AN: 6744

GnomAD4 genome AF: 0.201 AC: 30654 AN: 152160 Hom.: 3819 Cov.: 32 AF XY: 0.206 AC XY: 15355 AN XY: 74392

African (AFR) AF: 0.0741 AC: 3076 AN: 41526

American (AMR) AF: 0.317 AC: 4840 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1149 AN: 3466

East Asian (EAS) AF: 0.464 AC: 2400 AN: 5170

South Asian (SAS) AF: 0.286 AC: 1380 AN: 4824

European-Finnish (FIN) AF: 0.181 AC: 1915 AN: 10578

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.222 AC: 15113 AN: 67990

Other (OTH) AF: 0.239 AC: 505 AN: 2112

Alfa AF: 0.224 Hom.: 5384

Bravo AF: 0.207

Asia WGS AF: 0.336 AC: 1168 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Aneurysm-osteoarthritis syndrome (1)
-	-	1	Loeys-Dietz syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.41
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs8031440; hg19: chr15-67483979;