dbSNP rs146747167: SOBP:p.Ile539Leu (chr6-107634459-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018013.4(SOBP):c.1615A>C(p.Ile539Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,458,390 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I539V) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SOBP
NM_018013.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.63

Publications

9 publications found

Variant links:

Genes affected

SOBP (HGNC:29256): (sine oculis binding protein homolog) The protein encoded by this gene is a nuclear zinc finger protein that is involved in development of the cochlea. Defects in this gene have also been linked to intellectual disability. [provided by RefSeq, Mar 2011]

SOBP Gene-Disease associations (from GenCC):

intellectual disability, anterior maxillary protrusion, and strabismus
Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
syndromic intellectual disability
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

SOBP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOBP	NM_018013.4 link	c.1615A>C	p.Ile539Leu	missense_variant	Exon 6 of 7	ENST00000317357.10	NP_060483.3	A7XYQ1Q24K27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOBP	ENST00000317357.10 link	c.1615A>C	p.Ile539Leu	missense_variant	Exon 6 of 7	5	NM_018013.4	ENSP00000318900.5		A7XYQ1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458390

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725644

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000199

AC:

AN:

50172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111850

Other (OTH)

AF:

0.00

AC:

AN:

60350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000907115), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.2

PhyloP100

6.6

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.6

REVEL

Benign

0.16

Sift

Benign

0.21

Sift4G

Benign

0.095

Polyphen

0.98

Vest4

0.66

MutPred

0.27

Gain of catalytic residue at I539 (P = 0.001);

MVP

0.092

ClinPred

0.93

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.33

gMVP

0.58

Mutation Taster

=70/30

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over