6-168526417-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001166412.2(SMOC2):c.328A>T(p.Ile110Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMOC2 NM_001166412.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64

Genes affected

SMOC2 (HGNC:20323): (SPARC related modular calcium binding 2) This gene encodes a member of the SPARC family (secreted protein acidic and rich in cysteine/osteonectin/BM-40), which are highly expressed during embryogenesis and wound healing. The gene product is a matricellular protein which promotes matrix assembly and can stimulate endothelial cell proliferation and migration, as well as angiogenic activity. Associated with pulmonary function, this secretory gene product contains a Kazal domain, two thymoglobulin type-1 domains, and two EF-hand calcium-binding domains. The encoded protein may serve as a target for controlling angiogenesis in tumor growth and myocardial ischemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMOC2	NM_001166412.2	c.328A>T	p.Ile110Phe	missense_variant	3/13	ENST00000356284.7
SMOC2	NM_022138.3	c.328A>T	p.Ile110Phe	missense_variant	3/13
SMOC2	XM_011536065.2	c.328A>T	p.Ile110Phe	missense_variant	3/13
SMOC2	XM_011536066.2	c.328A>T	p.Ile110Phe	missense_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMOC2	ENST00000356284.7	c.328A>T	p.Ile110Phe	missense_variant	3/13	1	NM_001166412.2	P3
SMOC2	ENST00000354536.9	c.328A>T	p.Ile110Phe	missense_variant	3/13	1		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2023

The c.328A>T (p.I110F) alteration is located in exon 3 (coding exon 3) of the SMOC2 gene. This alteration results from a A to T substitution at nucleotide position 328, causing the isoleucine (I) at amino acid position 110 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.53		Gain of disorder (P = 0.1523);Gain of disorder (P = 0.1523);
MVP		0.66
MPC		0.56
ClinPred		0.98	D
GERP RS		3.7
Varity_R		0.62
gMVP		0.47

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: chr6-168927097;