chr14-69952268-C-T

Position:

chr14-69952268-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001034852.3(SMOC1):c.230C>T(p.Pro77Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,614,152 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 6 hom. )

Consequence

SMOC1
NM_001034852.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.83

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004329473).

BP6

Variant 14-69952268-C-T is Benign according to our data. Variant chr14-69952268-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282562.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr14-69952268-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00167 (254/152278) while in subpopulation NFE AF= 0.00291 (198/68026). AF 95% confidence interval is 0.00258. There are 2 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SMOC1	NM_001034852.3 linkuse as main transcript	c.230C>T	p.Pro77Leu	missense_variant	2/12	ENST00000361956.8
SMOC1	NM_022137.6 linkuse as main transcript	c.230C>T	p.Pro77Leu	missense_variant	2/12
SMOC1	XM_005267995.2 linkuse as main transcript	c.230C>T	p.Pro77Leu	missense_variant	2/12
SMOC1	XM_005267996.2 linkuse as main transcript	c.230C>T	p.Pro77Leu	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMOC1	ENST00000361956.8 linkuse as main transcript	c.230C>T	p.Pro77Leu	missense_variant	2/12	1	NM_001034852.3	A2	Q9H4F8-2
SMOC1	ENST00000381280.4 linkuse as main transcript	c.230C>T	p.Pro77Leu	missense_variant	2/12	1		P4	Q9H4F8-1
SMOC1	ENST00000553839.1 linkuse as main transcript	n.132C>T		non_coding_transcript_exon_variant	1/4	5
SMOC1	ENST00000555917.1 linkuse as main transcript	n.535C>T		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

255

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00293

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00179

AC:

449

AN:

251304

Hom.:

AF XY:

0.00158

AC XY:

214

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.00336

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00278

AC:

4068

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

1916

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.000765

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00118

Gnomad4 NFE exome

AF:

0.00343

Gnomad4 OTH exome

AF:

0.00212

GnomAD4 genome

AF:

0.00167

AC:

254

AN:

152278

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

109

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00291

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00280

Hom.:

Bravo

AF:

0.00164

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00200

AC:

243

EpiCase

AF:

0.00300

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2017	The P77L variant in the SMOC1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The NHLBI ESP Exome Sequencing Project reports that P77L was observed in 22/8,600 alleles (0.3%) from individuals of European American background, with no homozygous individuals, indicating it may be a rare variant in this population. The P77L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P77L as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SMOC1: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2015	- -

SMOC1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.22

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.0064

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-4.1

D;D

REVEL

Benign

0.089

Sift

Benign

0.13

T;T

Sift4G

Uncertain

0.048

D;D

Polyphen

0.48

P;B

Vest4

0.15

MVP

0.17

MPC

0.34

ClinPred

0.049

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over