2-219557459-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015311.3(OBSL1):c.3950T>A(p.Leu1317Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,548,662 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1317R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0077 ( 15 hom., cov: 34)

Exomes 𝑓: 0.00085 ( 19 hom. )

Consequence

OBSL1
NM_015311.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.54

Publications

2 publications found

Variant links:

Genes affected

OBSL1 (HGNC:29092): (obscurin like cytoskeletal adaptor 1) Cytoskeletal adaptor proteins function in linking the internal cytoskeleton of cells to the cell membrane. This gene encodes a cytoskeletal adaptor protein, which is a member of the Unc-89/obscurin family. The protein contains multiple N- and C-terminal immunoglobulin (Ig)-like domains and a central fibronectin type 3 domain. Mutations in this gene cause 3M syndrome type 2. Alternatively spliced transcript variants encoding different isoforms have been found in this gene. [provided by RefSeq, Mar 2010]

OBSL1 Gene-Disease associations (from GenCC):

3M syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
3-M syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OBSL1 links:

ENSG00000269068 (HGNC:):

ENSG00000269068 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 (MetaRNN=0.00804615).

BP6

Variant 2-219557459-A-T is Benign according to our data. Variant chr2-219557459-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 334490.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 = 0.0077 (1173/152292) while in subpopulation AFR AF = 0.026 (1081/41572). AF 95% confidence interval is 0.0247. There are 15 homozygotes in GnomAd4. There are 546 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OBSL1	NM_015311.3 link	c.3950T>A	p.Leu1317Gln	missense_variant	Exon 12 of 21	ENST00000404537.6	NP_056126.1	O75147-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OBSL1	ENST00000404537.6 link	c.3950T>A	p.Leu1317Gln	missense_variant	Exon 12 of 21	1	NM_015311.3	ENSP00000385636.1		O75147-3

Frequencies

GnomAD3 genomes

AF:

0.00769

AC:

1170

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0260

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00812

GnomAD2 exomes

AF:

0.00165

AC:

243

AN:

147334

AF XY:

0.00134

show subpopulations

Gnomad AFR exome

AF:

0.0268

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.000119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000706

GnomAD4 exome

AF:

0.000850

AC:

1187

AN:

1396370

Hom.:

Cov.:

AF XY:

0.000743

AC XY:

512

AN XY:

689054

show subpopulations

African (AFR)

AF:

0.0288

AC:

910

AN:

31608

American (AMR)

AF:

0.00185

AC:

AN:

35758

Ashkenazi Jewish (ASJ)

AF:

0.000159

AC:

AN:

25152

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35746

South Asian (SAS)

AF:

0.0000505

AC:

AN:

79240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46018

Middle Eastern (MID)

AF:

0.00263

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000639

AC:

AN:

1079174

Other (OTH)

AF:

0.00204

AC:

118

AN:

57976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00770

AC:

1173

AN:

152292

Hom.:

Cov.:

AF XY:

0.00733

AC XY:

546

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0260

AC:

1081

AN:

41572

American (AMR)

AF:

0.00386

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68014

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

106

158

211

264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000337

Hom.:

Bravo

AF:

0.00872

ESP6500AA

AF:

0.0222

AC:

ESP6500EA

AF:

0.000251

AC:

ExAC

AF:

0.000867

AC:

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

3M syndrome 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0080

T;T

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

3.5

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.5

D;.

REVEL

Uncertain

0.48

Sift

Benign

0.096

T;.

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;.

Vest4

0.58

MVP

0.76

MPC

0.69

ClinPred

0.027

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.71

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over