19-16829512-C-T

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.92C>T(p.Ser31Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,073,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: SIN3B NM_001297595.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

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=0.25870925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIN3B	NM_001297595.2	c.92C>T	p.Ser31Phe	missense_variant	1/19	ENST00000248054.10
SIN3B	NM_015260.4	c.92C>T	p.Ser31Phe	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIN3B	ENST00000248054.10	c.92C>T	p.Ser31Phe	missense_variant	1/19	1	NM_001297595.2	P1
SIN3B	ENST00000379803.5	c.92C>T	p.Ser31Phe	missense_variant	1/20	1
SIN3B	ENST00000596802.5	c.92C>T	p.Ser31Phe	missense_variant	1/8	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1073958 Hom.: 0 Cov.: 31 AF XY: 0.00000394 AC XY: 2 AN XY: 507238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000218

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Invitae

Sep 06, 2023

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 31 of the SIN3B protein (p.Ser31Phe). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with SIN3B-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Benign	-0.023
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	0.74	N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N;.;N
REVEL	Benign	0.052
Sift	Uncertain	0.022	D;.;D
Sift4G	Uncertain	0.051	T;D;T
Polyphen		0.52	P;.;D
Vest4		0.15
MutPred		0.28		Loss of glycosylation at S31 (P = 0.0211);Loss of glycosylation at S31 (P = 0.0211);Loss of glycosylation at S31 (P = 0.0211);
MVP		0.26
MPC		0.93
ClinPred		0.90	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs1971249953; hg19: chr19-16940323;