13-36867311-G-T

Position:

• chr13-36867311-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127217.3(SMAD9):​c.743C>A​(p.Thr248Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,551,172 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (185 hom.)
• Consequence: SMAD9 NM_001127217.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002430439).
• BP6: Variant 13-36867311-G-T is Benign according to our data. Variant chr13-36867311-G-T is described in ClinVar as [Benign]. Clinvar id is 311902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD9	NM_001127217.3	c.743C>A	p.Thr248Lys	missense_variant	4/7	ENST00000379826.5	NP_001120689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD9	ENST00000379826.5	c.743C>A	p.Thr248Lys	missense_variant	4/7	5	NM_001127217.3	ENSP00000369154	P1
SMAD9	ENST00000350148.10	c.671-1553C>A		intron_variant		1		ENSP00000239885
SMAD9	ENST00000399275.7	c.*381-1553C>A		intron_variant, NMD_transcript_variant		1		ENSP00000382216

Frequencies

GnomAD3 genomes AF: 0.00694 AC: 1057 AN: 152216 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0600

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0154 AC: 2408 AN: 156448 Hom.: 144 AF XY: 0.0125 AC XY: 1037 AN XY: 82920

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.0917

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00615

Gnomad SAS exome AF: 0.00145

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00729

GnomAD4 exome AF: 0.00273 AC: 3816 AN: 1398838 Hom.: 185 Cov.: 29 AF XY: 0.00251 AC XY: 1732 AN XY: 689954

Gnomad4 AFR exome AF: 0.000633

Gnomad4 AMR exome AF: 0.0876

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00476

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.0000406

Gnomad4 NFE exome AF: 0.000206

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.00704 AC: 1072 AN: 152334 Hom.: 40 Cov.: 32 AF XY: 0.00835 AC XY: 622 AN XY: 74494

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.0608

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00520

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00118 Hom.: 10

Bravo AF: 0.0123

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.00133 AC: 33

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pulmonary hypertension, primary, 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Benign	0.32
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.77
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.41	.;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.27
Sift	Benign	0.50	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.0050	B;B
Vest4		0.21
MPC		0.28
ClinPred		0.0013	T
GERP RS		2.6
Varity_R		0.035
gMVP		0.37

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: rs79733377; hg19: chr13-37441448; COSMIC: COSV63204740;