rs4776342

Variant names:

• chr15-67126053-A-G
• rs4776342
• NM_005902.4:c.207-38842A>G

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.207-38842A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 779,918 control chromosomes in the GnomAD database, including 24,400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7883 hom., cov: 32)
  • Exomes 𝑓: 0.22 (16517 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.96
• 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=-0.92).
• BP6: Variant 15-67126053-A-G is Benign according to our data. Variant chr15-67126053-A-G is described in ClinVar as Benign. ClinVar VariationId is 1256793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.207-38842A>G		intron_variant	Intron 1 of 8	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.207-38842A>G		intron_variant	Intron 1 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46386 AN: 151922 Hom.: 7868 Cov.: 32

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.326

GnomAD4 exome AF: 0.224 AC: 140544 AN: 627878 Hom.: 16517 AF XY: 0.224 AC XY: 65680 AN XY: 293228

African (AFR) AF: 0.427 AC: 5120 AN: 11998

American (AMR) AF: 0.368 AC: 275 AN: 748

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 1289 AN: 3832

East Asian (EAS) AF: 0.605 AC: 1769 AN: 2924

South Asian (SAS) AF: 0.418 AC: 5331 AN: 12746

European-Finnish (FIN) AF: 0.176 AC: 36 AN: 204

Middle Eastern (MID) AF: 0.333 AC: 418 AN: 1256

European-Non Finnish (NFE) AF: 0.210 AC: 120670 AN: 573682

Other (OTH) AF: 0.275 AC: 5636 AN: 20488

GnomAD4 genome AF: 0.305 AC: 46443 AN: 152040 Hom.: 7883 Cov.: 32 AF XY: 0.308 AC XY: 22890 AN XY: 74322

African (AFR) AF: 0.400 AC: 16582 AN: 41434

American (AMR) AF: 0.356 AC: 5443 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1161 AN: 3470

East Asian (EAS) AF: 0.606 AC: 3130 AN: 5166

South Asian (SAS) AF: 0.436 AC: 2095 AN: 4804

European-Finnish (FIN) AF: 0.172 AC: 1826 AN: 10590

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.224 AC: 15245 AN: 67984

Other (OTH) AF: 0.324 AC: 684 AN: 2110

Alfa AF: 0.259 Hom.: 1156

Bravo AF: 0.324

Asia WGS AF: 0.488 AC: 1694 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 28, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.059
DANN	Benign	0.25
PhyloP100		-4.0
PromoterAI		0.042	Neutral
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: rs4776342; hg19: chr15-67418391;