13-36867311-G-C

Variant names:

• chr13-36867311-G-C
• NM_001127217.3:c.743C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127217.3(SMAD9):​c.743C>G​(p.Thr248Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SMAD9 NM_001127217.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.178498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD9	NM_001127217.3	c.743C>G	p.Thr248Arg	missense_variant	Exon 4 of 7	ENST00000379826.5	NP_001120689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD9	ENST00000379826.5	c.743C>G	p.Thr248Arg	missense_variant	Exon 4 of 7	5	NM_001127217.3	ENSP00000369154.4
SMAD9	ENST00000350148.10	c.671-1553C>G		intron_variant	Intron 3 of 5	1		ENSP00000239885.6
SMAD9	ENST00000399275.7	n.*381-1553C>G		intron_variant	Intron 3 of 5	1		ENSP00000382216.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398850 Hom.: 0 Cov.: 29 AF XY: 0.00000145 AC XY: 1 AN XY: 689958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Benign	0.58
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.76
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.45	.;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.45	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.29	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.025	B;B
Vest4		0.19
MutPred		0.37		Gain of catalytic residue at V253 (P = 0.0096);Gain of catalytic residue at V253 (P = 0.0096);
MVP		0.91
MPC		0.26
ClinPred		0.068	T
GERP RS		2.6
Varity_R		0.052
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-37441448;