14-69952282-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001034852.3(SMOC1):c.244G>A(p.Val82Met) variant causes a missense change. The variant allele was found at a frequency of 0.00096 in 1,614,176 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0046 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (3 hom.)
• Consequence: SMOC1 NM_001034852.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.75

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008308232).
• BP6: Variant 14-69952282-G-A is Benign according to our data. Variant chr14-69952282-G-A is described in ClinVar as [Benign]. Clinvar id is 789814.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-69952282-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0046 (701/152310) while in subpopulation AFR AF= 0.0155 (643/41564). AF 95% confidence interval is 0.0145. There are 4 homozygotes in gnomad4. There are 334 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMOC1	NM_001034852.3	c.244G>A	p.Val82Met	missense_variant	2/12	ENST00000361956.8
SMOC1	NM_022137.6	c.244G>A	p.Val82Met	missense_variant	2/12
SMOC1	XM_005267995.2	c.244G>A	p.Val82Met	missense_variant	2/12
SMOC1	XM_005267996.2	c.244G>A	p.Val82Met	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMOC1	ENST00000361956.8	c.244G>A	p.Val82Met	missense_variant	2/12	1	NM_001034852.3	A2
SMOC1	ENST00000381280.4	c.244G>A	p.Val82Met	missense_variant	2/12	1		P4
SMOC1	ENST00000553839.1	n.146G>A		non_coding_transcript_exon_variant	1/4	5
SMOC1	ENST00000555917.1	n.549G>A		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 700 AN: 152192 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00123 AC: 310 AN: 251292 Hom.: 3 AF XY: 0.000957 AC XY: 130 AN XY: 135804

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000580 AC: 848 AN: 1461866 Hom.: 3 Cov.: 33 AF XY: 0.000505 AC XY: 367 AN XY: 727240

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000881

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00460 AC: 701 AN: 152310 Hom.: 4 Cov.: 33 AF XY: 0.00448 AC XY: 334 AN XY: 74478

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.000917 Hom.: 1

Bravo AF: 0.00553

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00141 AC: 171

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.53	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.092
Sift	Benign	0.058	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.61	P;D
Vest4		0.32
MVP		0.57
MPC		0.70
ClinPred		0.021	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10150925; hg19: chr14-70418999;