Genetic Variant NM_015311.3:c.5657G>C (chr2-219551555-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015311.3(OBSL1):c.5657G>C(p.Ser1886Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1886G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

OBSL1
NM_015311.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.18

Publications

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

OBSL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1871827).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015311.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	NM_015311.3	MANE Select	c.5657G>C	p.Ser1886Thr	missense	Exon 20 of 21	NP_056126.1	O75147-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OBSL1	ENST00000404537.6	TSL:1 MANE Select	c.5657G>C	p.Ser1886Thr	missense	Exon 20 of 21	ENSP00000385636.1	O75147-3
OBSL1	ENST00000953546.1		c.5669G>C	p.Ser1890Thr	missense	Exon 20 of 21	ENSP00000623605.1
OBSL1	ENST00000953548.1		c.5600G>C	p.Ser1867Thr	missense	Exon 20 of 21	ENSP00000623607.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446746

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33200

American (AMR)

AF:

0.00

AC:

AN:

42646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25774

East Asian (EAS)

AF:

0.00

AC:

AN:

38928

South Asian (SAS)

AF:

0.00

AC:

AN:

83570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52026

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1105066

Other (OTH)

AF:

0.00

AC:

AN:

59792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.012

Eigen

Benign

0.18

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.70

M_CAP

Benign

0.018

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

PhyloP100

1.2

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.50

REVEL

Benign

0.10

Sift

Benign

1.0

Sift4G

Benign

0.57

Polyphen

1.0

Vest4

0.43

MutPred

0.41

Loss of disorder (P = 0.1562)

MVP

0.18

MPC

0.61

ClinPred

0.59

GERP RS

3.5

Varity_R

0.082

gMVP

0.35

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over