rs1365818420

Variant names:

• chr14-70010946-G-A
• rs1365818420
• NM_001034852.3:c.857G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001034852.3(SMOC1):​c.857G>A​(p.Arg286His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,459,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R286R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SMOC1 NM_001034852.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.06
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 14-70010946-G-A is Pathogenic according to our data. Variant chr14-70010946-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 562137.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMOC1	NM_001034852.3	c.857G>A	p.Arg286His	missense_variant, splice_region_variant	Exon 8 of 12	ENST00000361956.8	NP_001030024.1
SMOC1	NM_001425244.1	c.890G>A	p.Arg297His	missense_variant, splice_region_variant	Exon 8 of 12		NP_001412173.1
SMOC1	NM_001425245.1	c.890G>A	p.Arg297His	missense_variant, splice_region_variant	Exon 8 of 12		NP_001412174.1
SMOC1	NM_022137.6	c.857G>A	p.Arg286His	missense_variant, splice_region_variant	Exon 8 of 12		NP_071420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMOC1	ENST00000361956.8	c.857G>A	p.Arg286His	missense_variant, splice_region_variant	Exon 8 of 12	1	NM_001034852.3	ENSP00000355110.4
SMOC1	ENST00000381280.4	c.857G>A	p.Arg286His	missense_variant, splice_region_variant	Exon 8 of 12	1		ENSP00000370680.4
SMOC1	ENST00000557483.1	n.435G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1459892 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726278

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4338

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60224

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Microphthalmia with limb anomalies Pathogenic:1

Laboratory of Medical Genetics, University of Torino

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Found in homozygosity

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0	.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	2.0	M;M
PhyloP100		8.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0090	D;D
Vest4		0.52
ClinPred		0.96	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.80
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1365818420; hg19: chr14-70477663; COSMIC: COSV62760517;