rs7333607

Variant names:

• chr13-36887873-A-G
• rs7333607
• NM_001127217.3:c.-186-7998T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127217.3(SMAD9):​c.-186-7998T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 152,076 control chromosomes in the GnomAD database, including 4,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as confers sensitivity (★).

• Frequency: Genomes: 𝑓 0.23 (4309 hom., cov: 31)
• Consequence: SMAD9 NM_001127217.3 intron
• Clinical Significance: confers sensitivity criteria provided, single submitter O:1
• Conservation: PhyloP100: -0.794
• Publications: 18 publications found

Genes affected

SMAD9 (HGNC:6774): (SMAD family member 9) The protein encoded by this gene is a member of the SMAD family, which transduces signals from TGF-beta family members. The encoded protein is activated by bone morphogenetic proteins and interacts with SMAD4. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

SMAD9 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pulmonary hypertension, primary, 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD9	NM_001127217.3	c.-186-7998T>C		intron_variant	Intron 1 of 6	ENST00000379826.5	NP_001120689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD9	ENST00000379826.5	c.-186-7998T>C		intron_variant	Intron 1 of 6	5	NM_001127217.3	ENSP00000369154.4
SMAD9	ENST00000350148.10	c.-186-7998T>C		intron_variant	Intron 1 of 5	1		ENSP00000239885.6
SMAD9	ENST00000715264.1	c.-186-7998T>C		intron_variant	Intron 1 of 6			ENSP00000520435.1
SMAD9	ENST00000483941.2	n.254-7998T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35499 AN: 151956 Hom.: 4308 Cov.: 31

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.0970

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.208

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.234 AC: 35516 AN: 152076 Hom.: 4309 Cov.: 31 AF XY: 0.231 AC XY: 17200 AN XY: 74316

African (AFR) AF: 0.274 AC: 11354 AN: 41476

American (AMR) AF: 0.201 AC: 3081 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 635 AN: 3472

East Asian (EAS) AF: 0.0972 AC: 502 AN: 5162

South Asian (SAS) AF: 0.164 AC: 788 AN: 4814

European-Finnish (FIN) AF: 0.255 AC: 2700 AN: 10570

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15856 AN: 67974

Other (OTH) AF: 0.210 AC: 442 AN: 2108

Alfa AF: 0.227 Hom.: 1824

Bravo AF: 0.227

Asia WGS AF: 0.171 AC: 595 AN: 3478

ClinVar

Significance: confers sensitivity

Submissions summary: Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lung cancer Other:1

May 01, 2012

Kong Lab, Department of Radiation Oncology, Case Western Reserve University School of Medicine

Significance: confers sensitivity

Review Status: criteria provided, single submitter

Collection Method: research

Improve the prediction accuracy for overal survival in non-small cell lung cancer patients -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.32
DANN	Benign	0.55
PhyloP100		-0.79
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: rs7333607; hg19: chr13-37462010;