19-16831643-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001297595.2(SIN3B):c.377G>A(p.Ser126Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIN3B NM_001297595.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.753

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SIN3B
• BP4: Computational evidence support a benign effect (MetaRNN=0.09018946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIN3B	NM_001297595.2	c.377G>A	p.Ser126Asn	missense_variant	3/19	ENST00000248054.10
SIN3B	NM_015260.4	c.377G>A	p.Ser126Asn	missense_variant	3/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIN3B	ENST00000248054.10	c.377G>A	p.Ser126Asn	missense_variant	3/19	1	NM_001297595.2	P1
SIN3B	ENST00000379803.5	c.377G>A	p.Ser126Asn	missense_variant	3/20	1
SIN3B	ENST00000596802.5	c.377G>A	p.Ser126Asn	missense_variant	3/8	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 23, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	13
Dann	Benign	0.94
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.090	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.21	N;.;N
REVEL	Benign	0.033
Sift	Benign	0.26	T;.;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0030	B;B;B
Vest4		0.14
MutPred		0.19		Loss of disorder (P = 0.1551);Loss of disorder (P = 0.1551);Loss of disorder (P = 0.1551);
MVP		0.33
MPC		0.79
ClinPred		0.047	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.024
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-16942454;