13-36879486-G-C

Position:

• chr13-36879486-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001127217.3(SMAD9):​c.204C>G​(p.Cys68Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: SMAD9 NM_001127217.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.370

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain MH1 (size 124) in uniprot entity SMAD9_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_001127217.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD9	NM_001127217.3	c.204C>G	p.Cys68Trp	missense_variant	2/7	ENST00000379826.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD9	ENST00000379826.5	c.204C>G	p.Cys68Trp	missense_variant	2/7	5	NM_001127217.3	P1
SMAD9	ENST00000350148.10	c.204C>G	p.Cys68Trp	missense_variant	2/6	1
SMAD9	ENST00000399275.7	c.204C>G	p.Cys68Trp	missense_variant, NMD_transcript_variant	1/6	1
SMAD9	ENST00000483941.2	n.643C>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.;D
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.52	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	4.0	H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-10	D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.96
MutPred		0.78		Gain of catalytic residue at R73 (P = 0);Gain of catalytic residue at R73 (P = 0);Gain of catalytic residue at R73 (P = 0);
MVP		1.0
MPC		0.98
ClinPred		1.0	D
GERP RS		-1.8
Varity_R		0.99
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs146583835; hg19: chr13-37453623;