chr19-16841807-A-C

Variant names:

• chr19-16841807-A-C
• rs1568413987
• NM_001297595.2:c.421A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001297595.2(SIN3B):​c.421A>C​(p.Lys141Gln) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SIN3B NM_001297595.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40
• Publications: 0 publications found

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

ACMG classification

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=0.09982252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIN3B	NM_001297595.2	c.421A>C	p.Lys141Gln	missense_variant	Exon 4 of 19	ENST00000248054.10	NP_001284524.1
SIN3B	NM_015260.4	c.421A>C	p.Lys141Gln	missense_variant	Exon 4 of 20		NP_056075.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIN3B	ENST00000248054.10	c.421A>C	p.Lys141Gln	missense_variant	Exon 4 of 19	1	NM_001297595.2	ENSP00000248054.4
SIN3B	ENST00000379803.5	c.421A>C	p.Lys141Gln	missense_variant	Exon 4 of 20	1		ENSP00000369131.1
SIN3B	ENST00000596802.5	c.421A>C	p.Lys141Gln	missense_variant	Exon 4 of 8	1		ENSP00000473039.1
SIN3B	ENST00000596638.1	c.-147A>C		upstream_gene_variant		5		ENSP00000472365.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.421A>C (p.K141Q) alteration is located in exon 4 (coding exon 4) of the SIN3B gene. This alteration results from a A to C substitution at nucleotide position 421, causing the lysine (K) at amino acid position 141 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.048	.;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L
PhyloP100		1.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.19	N;.;N
REVEL	Benign	0.054
Sift	Benign	0.56	T;.;T
Sift4G	Benign	0.65	T;T;T
Polyphen		0.0070	B;B;B
Vest4		0.35
MutPred		0.32		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		0.42
MPC		0.92
ClinPred		0.093	T
GERP RS		4.3
PromoterAI		-0.0048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.41
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1568413987; hg19: chr19-16952618;