14-69952141-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001034852.3(SMOC1):c.103C>G(p.Leu35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,614,174 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: SMOC1 NM_001034852.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.19

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01919642).
• BP6: Variant 14-69952141-C-G is Benign according to our data. Variant chr14-69952141-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 769863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00145 (221/152312) while in subpopulation AMR AF= 0.00209 (32/15302). AF 95% confidence interval is 0.00178. There are 1 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMOC1	NM_001034852.3	c.103C>G	p.Leu35Val	missense_variant	2/12	ENST00000361956.8
SMOC1	NM_022137.6	c.103C>G	p.Leu35Val	missense_variant	2/12
SMOC1	XM_005267995.2	c.103C>G	p.Leu35Val	missense_variant	2/12
SMOC1	XM_005267996.2	c.103C>G	p.Leu35Val	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMOC1	ENST00000361956.8	c.103C>G	p.Leu35Val	missense_variant	2/12	1	NM_001034852.3	A2
SMOC1	ENST00000381280.4	c.103C>G	p.Leu35Val	missense_variant	2/12	1		P4
SMOC1	ENST00000553839.1	n.5C>G		non_coding_transcript_exon_variant	1/4	5
SMOC1	ENST00000555917.1	n.408C>G		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00111 AC: 280 AN: 251420 Hom.: 2 AF XY: 0.000979 AC XY: 133 AN XY: 135884

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00207 AC: 3025 AN: 1461862 Hom.: 7 Cov.: 31 AF XY: 0.00193 AC XY: 1407 AN XY: 727238

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00246

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74474

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00145

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00119 AC: 144

EpiCase AF: 0.00125

EpiControl AF: 0.00213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	SMOC1: BS2 -

SMOC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.98	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.85	N;N
REVEL	Benign	0.13
Sift	Benign	0.090	T;T
Sift4G	Uncertain	0.040	D;D
Polyphen		0.95	P;D
Vest4		0.66
MVP		0.73
MPC		0.32
ClinPred		0.014	T
GERP RS		4.5
Varity_R		0.15
gMVP		0.40

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: rs139737624; hg19: chr14-70418858;