rs1365818420

Positions:

• chr14-70010946-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 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).

• 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

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius 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 id is 562137.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMOC1	NM_001034852.3	c.857G>A	p.Arg286His	missense_variant, splice_region_variant	8/12	ENST00000361956.8	NP_001030024.1
SMOC1	NM_022137.6	c.857G>A	p.Arg286His	missense_variant, splice_region_variant	8/12		NP_071420.1
SMOC1	XM_005267995.2	c.890G>A	p.Arg297His	missense_variant, splice_region_variant	8/12		XP_005268052.1
SMOC1	XM_005267996.2	c.890G>A	p.Arg297His	missense_variant, splice_region_variant	8/12		XP_005268053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMOC1	ENST00000361956.8	c.857G>A	p.Arg286His	missense_variant, splice_region_variant	8/12	1	NM_001034852.3	ENSP00000355110	A2
SMOC1	ENST00000381280.4	c.857G>A	p.Arg286His	missense_variant, splice_region_variant	8/12	1		ENSP00000370680	P4
SMOC1	ENST00000557483.1	n.435G>A		splice_region_variant, non_coding_transcript_exon_variant	2/3	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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Pathogenic, no assertion criteria provided

literature only

Laboratory of Medical Genetics, University of Torino

-

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	0.37	.;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
MutationTaster	Benign	1.0	D;D
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
Polyphen		1.0	D;D
Vest4		0.52
MutPred		0.57		Gain of glycosylation at T283 (P = 0.0468);Gain of glycosylation at T283 (P = 0.0468);
MVP		0.93
MPC		0.38
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

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

Publications

LitVar

Other links and lift over

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