Genetic Variant SIN3B:p.Lys141Glu (chr19-16841807-A-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_001297595.2(SIN3B):c.421A>G(p.Lys141Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 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. K141Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SIN3B
NM_001297595.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.40

Publications

0 publications found

Variant links:

Genes affected

SIN3B (HGNC:19354): (SIN3 transcription regulator family member B) Predicted to enable transcription corepressor activity. Predicted to be involved in histone deacetylation; negative regulation of transcription by RNA polymerase II; and striated muscle tissue development. Predicted to be located in nucleus. Predicted to be part of Sin3 complex. Predicted to be active in chromatin. [provided by Alliance of Genome Resources, Apr 2022]

SIN3B Gene-Disease associations (from GenCC):

SIN3A-related intellectual disability syndrome due to a point mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
syndromic intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: G2P

SIN3B 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=0.08779392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIN3B	NM_001297595.2 link	c.421A>G	p.Lys141Glu	missense_variant	Exon 4 of 19	ENST00000248054.10	NP_001284524.1	O75182-2
SIN3B	NM_015260.4 link	c.421A>G	p.Lys141Glu	missense_variant	Exon 4 of 20		NP_056075.1	O75182-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIN3B	ENST00000248054.10 link	c.421A>G	p.Lys141Glu	missense_variant	Exon 4 of 19	1	NM_001297595.2	ENSP00000248054.4	O75182-2
SIN3B	ENST00000379803.5 link	c.421A>G	p.Lys141Glu	missense_variant	Exon 4 of 20	1		ENSP00000369131.1	O75182-1
SIN3B	ENST00000596802.5 link	c.421A>G	p.Lys141Glu	missense_variant	Exon 4 of 8	1		ENSP00000473039.1	O75182-3
SIN3B	ENST00000596638.1 link	c.-147A>G		upstream_gene_variant		5		ENSP00000472365.1	M0R271

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.069

.;.;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.0072

MetaRNN

Benign

0.088

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;L

PhyloP100

1.4

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.52

N;.;N

REVEL

Benign

0.095

Sift

Benign

0.48

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.25

MutPred

0.26

Loss of ubiquitination at K141 (P = 0.0039);Loss of ubiquitination at K141 (P = 0.0039);Loss of ubiquitination at K141 (P = 0.0039);

MVP

0.24

MPC

1.2

ClinPred

0.10

GERP RS

4.3

PromoterAI

-0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.47

Mutation Taster

=88/12

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