dbSNP rs11846426: SMOC1:p.Phe387Leu (chr14-70023317-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001034852.3(SMOC1):c.1161C>G(p.Phe387Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F387F) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SMOC1
NM_001034852.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.29

Publications

0 publications found

Variant links:

Genes affected

SMOC1 (HGNC:20318): (SPARC related modular calcium binding 1) This gene encodes a multi-domain secreted protein that may have a critical role in ocular and limb development. Mutations in this gene are associated with microphthalmia and limb anomalies. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

SMOC1 Gene-Disease associations (from GenCC):

microphthalmia with limb anomalies
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

SMOC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24955392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMOC1	NM_001034852.3 link	c.1161C>G	p.Phe387Leu	missense_variant	Exon 11 of 12	ENST00000361956.8	NP_001030024.1	Q9H4F8-2
SMOC1	NM_001425244.1 link	c.1194C>G	p.Phe398Leu	missense_variant	Exon 11 of 12		NP_001412173.1
SMOC1	NM_001425245.1 link	c.1194C>G	p.Phe398Leu	missense_variant	Exon 11 of 12		NP_001412174.1
SMOC1	NM_022137.6 link	c.1161C>G	p.Phe387Leu	missense_variant	Exon 11 of 12		NP_071420.1	Q9H4F8-1A0A024R6E0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMOC1	ENST00000361956.8 link	c.1161C>G	p.Phe387Leu	missense_variant	Exon 11 of 12	1	NM_001034852.3	ENSP00000355110.4		Q9H4F8-2
SMOC1	ENST00000381280.4 link	c.1161C>G	p.Phe387Leu	missense_variant	Exon 11 of 12	1		ENSP00000370680.4		Q9H4F8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

.;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N

PhyloP100

1.3

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-4.3

D;D

REVEL

Benign

0.11

Sift

Benign

0.084

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.69

P;B

Vest4

0.25

MutPred

0.50

Loss of methylation at K392 (P = 0.1108);Loss of methylation at K392 (P = 0.1108);

MVP

0.44

MPC

0.57

ClinPred

0.82

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.67

Mutation Taster

=41/59

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over