rs16950635

Variant names:

• chr15-67125867-G-A
• rs16950635
• ENST00000540846.6:c.-227G>A

Variant summary

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

The ENST00000540846.6(SMAD3):​c.-227G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0491 in 985,320 control chromosomes in the GnomAD database, including 1,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (611 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1001 hom.)
• Consequence: SMAD3 ENST00000540846.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.54
• Publications: 17 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: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 15-67125867-G-A is Benign according to our data. Variant chr15-67125867-G-A is described in ClinVar as Benign. ClinVar VariationId is 1288852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000540846.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.207-39028G>A		intron	N/A	NP_005893.1
	SMAD3	NM_001145102.2		c.-227G>A		5_prime_UTR	Exon 1 of 9	NP_001138574.1
	SMAD3	NM_001407015.1		c.-227G>A		5_prime_UTR	Exon 1 of 8	NP_001393944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000540846.6	TSL:1	c.-227G>A		5_prime_UTR	Exon 1 of 9	ENSP00000437757.2
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.207-39028G>A		intron	N/A	ENSP00000332973.4
	SMAD3	ENST00000560424.2	TSL:3	c.207-39028G>A		intron	N/A	ENSP00000455540.2

Frequencies

GnomAD3 genomes AF: 0.0765 AC: 11626 AN: 152036 Hom.: 611 Cov.: 32

Gnomad AFR AF: 0.0899

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0464

Gnomad OTH AF: 0.0796

GnomAD4 exome AF: 0.0441 AC: 36767 AN: 833166 Hom.: 1001 Cov.: 30 AF XY: 0.0440 AC XY: 16912 AN XY: 384756

African (AFR) AF: 0.0984 AC: 1554 AN: 15786

American (AMR) AF: 0.128 AC: 126 AN: 986

Ashkenazi Jewish (ASJ) AF: 0.0662 AC: 341 AN: 5152

East Asian (EAS) AF: 0.262 AC: 976 AN: 3724

South Asian (SAS) AF: 0.148 AC: 2436 AN: 16458

European-Finnish (FIN) AF: 0.0399 AC: 11 AN: 276

Middle Eastern (MID) AF: 0.0667 AC: 108 AN: 1620

European-Non Finnish (NFE) AF: 0.0388 AC: 29544 AN: 761864

Other (OTH) AF: 0.0612 AC: 1671 AN: 27300

GnomAD4 genome AF: 0.0766 AC: 11649 AN: 152154 Hom.: 611 Cov.: 32 AF XY: 0.0790 AC XY: 5876 AN XY: 74392

African (AFR) AF: 0.0901 AC: 3739 AN: 41492

American (AMR) AF: 0.119 AC: 1814 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0680 AC: 236 AN: 3470

East Asian (EAS) AF: 0.254 AC: 1312 AN: 5160

South Asian (SAS) AF: 0.162 AC: 778 AN: 4808

European-Finnish (FIN) AF: 0.0365 AC: 387 AN: 10602

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0464 AC: 3153 AN: 68008

Other (OTH) AF: 0.0802 AC: 169 AN: 2108

Alfa AF: 0.0638 Hom.: 610

Bravo AF: 0.0831

Asia WGS AF: 0.171 AC: 592 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	17
DANN	Benign	0.79
PhyloP100		2.5
PromoterAI		-0.024	Neutral
Mutation Taster		=300/0	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: rs16950635; hg19: chr15-67418205;