14-69952268-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.83

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]

ACMG classification

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=3, 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 GnomAd at 2 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152160 Hom.: 2 Cov.: 32

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.: 0 AF XY: 0.00158 AC XY: 214 AN XY: 135808

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.: 6 Cov.: 33 AF XY: 0.00263 AC XY: 1916 AN XY: 727242

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.: 2 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74470

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.: 1

Bravo AF: 0.00164

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00200 AC: 243

EpiCase AF: 0.00300

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2015	- -
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	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SMOC1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

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	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	20
Dann	Benign	0.75
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
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	T
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

Other links and lift over

dbSNP: rs143606483; hg19: chr14-70418985;