Genetic Variant SMOC1:c.1046+7T>A (chr14-70013498-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001034852.3(SMOC1):c.1046+7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,612,844 control chromosomes in the GnomAD database, including 23,863 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3509 hom., cov: 32)

Exomes 𝑓: 0.16 ( 20354 hom. )

Consequence

SMOC1
NM_001034852.3 splice_region, intron

Scores

Splicing: ADA: 0.00006533

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.137

Publications

7 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P

SMOC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 14-70013498-T-A is Benign according to our data. Variant chr14-70013498-T-A is described in ClinVar as Benign. ClinVar VariationId is 257186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034852.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SMOC1	NM_001034852.3	MANE Select	c.1046+7T>A	splice_region intron	N/A	NP_001030024.1	Q9H4F8-2
SMOC1	NM_001425244.1		c.1079+7T>A	splice_region intron	N/A	NP_001412173.1
SMOC1	NM_001425245.1		c.1079+7T>A	splice_region intron	N/A	NP_001412174.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SMOC1	ENST00000361956.8	TSL:1 MANE Select	c.1046+7T>A	splice_region intron	N/A	ENSP00000355110.4	Q9H4F8-2
SMOC1	ENST00000381280.4	TSL:1	c.1046+7T>A	splice_region intron	N/A	ENSP00000370680.4	Q9H4F8-1
SMOC1	ENST00000853906.1		c.1094+7T>A	splice_region intron	N/A	ENSP00000523965.1

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30567

AN:

151814

Hom.:

3511

Cov.:

show subpopulations

Gnomad AFR

AF:

0.307

Gnomad AMI

AF:

0.100

Gnomad AMR

AF:

0.171

Gnomad ASJ

AF:

0.160

Gnomad EAS

AF:

0.0170

Gnomad SAS

AF:

0.0441

Gnomad FIN

AF:

0.215

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.193

GnomAD2 exomes

AF:

0.153

AC:

38477

AN:

251140

AF XY:

0.146

show subpopulations

Gnomad AFR exome

AF:

0.311

Gnomad AMR exome

AF:

0.160

Gnomad ASJ exome

AF:

0.162

Gnomad EAS exome

AF:

0.00881

Gnomad FIN exome

AF:

0.212

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.166

GnomAD4 exome

AF:

0.160

AC:

233640

AN:

1460912

Hom.:

20354

Cov.:

AF XY:

0.156

AC XY:

113388

AN XY:

726832

show subpopulations

African (AFR)

AF:

0.316

AC:

10576

AN:

33458

American (AMR)

AF:

0.161

AC:

7184

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.162

AC:

4241

AN:

26132

East Asian (EAS)

AF:

0.0233

AC:

926

AN:

39698

South Asian (SAS)

AF:

0.0503

AC:

4335

AN:

86248

European-Finnish (FIN)

AF:

0.209

AC:

11147

AN:

53306

Middle Eastern (MID)

AF:

0.200

AC:

1149

AN:

5750

European-Non Finnish (NFE)

AF:

0.166

AC:

184546

AN:

1111246

Other (OTH)

AF:

0.158

AC:

9536

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

9996

19991

29987

39982

49978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6484

12968

19452

25936

32420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.201

AC:

30591

AN:

151932

Hom.:

3509

Cov.:

AF XY:

0.198

AC XY:

14678

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.307

AC:

12700

AN:

41416

American (AMR)

AF:

0.171

AC:

2602

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.160

AC:

556

AN:

3466

East Asian (EAS)

AF:

0.0168

AC:

AN:

5164

South Asian (SAS)

AF:

0.0439

AC:

211

AN:

4808

European-Finnish (FIN)

AF:

0.215

AC:

2267

AN:

10544

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.171

AC:

11609

AN:

67964

Other (OTH)

AF:

0.192

AC:

405

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1238

2476

3713

4951

6189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

300

600

900

1200

1500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.130

Hom.:

481

Bravo

AF:

0.205

Asia WGS

AF:

0.0650

AC:

229

AN:

3478

EpiCase

AF:

0.161

EpiControl

AF:

0.157

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000065

dbscSNV1_RF

Benign

0.11

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: 1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over