14-69952201-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001034852.3(SMOC1):c.163A>T(p.Ile55Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,614,116 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: SMOC1 NM_001034852.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.33

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018483818).
• BP6: Variant 14-69952201-A-T is Benign according to our data. Variant chr14-69952201-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 737631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00129 (197/152234) while in subpopulation AFR AF= 0.00455 (189/41526). AF 95% confidence interval is 0.00402. There are 1 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMOC1	NM_001034852.3	c.163A>T	p.Ile55Phe	missense_variant	2/12	ENST00000361956.8
SMOC1	NM_022137.6	c.163A>T	p.Ile55Phe	missense_variant	2/12
SMOC1	XM_005267995.2	c.163A>T	p.Ile55Phe	missense_variant	2/12
SMOC1	XM_005267996.2	c.163A>T	p.Ile55Phe	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMOC1	ENST00000361956.8	c.163A>T	p.Ile55Phe	missense_variant	2/12	1	NM_001034852.3	A2
SMOC1	ENST00000381280.4	c.163A>T	p.Ile55Phe	missense_variant	2/12	1		P4
SMOC1	ENST00000553839.1	n.65A>T		non_coding_transcript_exon_variant	1/4	5
SMOC1	ENST00000555917.1	n.468A>T		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 197 AN: 152116 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000358 AC: 90 AN: 251364 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135842

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1461882 Hom.: 1 Cov.: 33 AF XY: 0.0000839 AC XY: 61 AN XY: 727244

Gnomad4 AFR exome AF: 0.00436

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152234 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74436

Gnomad4 AFR AF: 0.00455

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000998 Hom.: 1

Bravo AF: 0.00161

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000428 AC: 52

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 23, 2023

- -

SMOC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 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	0.14
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.92	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.071
Sift	Benign	0.21	T;T
Sift4G	Uncertain	0.012	D;D
Polyphen		0.068	B;B
Vest4		0.30
MVP		0.21
MPC		0.61
ClinPred		0.045	T
GERP RS		0.48
Varity_R		0.19
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs143490732; hg19: chr14-70418918; COSMIC: COSV105280356;