NM_001145358.2:c.3653C>G

Variant names:

• chr15-75372148-G-C
• NM_001145358.2:c.3653C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001145358.2(SIN3A):​c.3653C>G​(p.Thr1218Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIN3A NM_001145358.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.90
• Publications: 0 publications found

Genes affected

SIN3A (HGNC:19353): (SIN3 transcription regulator family member A) The protein encoded by this gene is a transcriptional regulatory protein. It contains paired amphipathic helix (PAH) domains, which are important for protein-protein interactions and may mediate repression by the Mad-Max complex. [provided by RefSeq, Jul 2008]

SIN3A Gene-Disease associations (from GenCC):

• SIN3A-related intellectual disability syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, ClinGen
• chromosome 15q24 deletion syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• SIN3A-related intellectual disability syndrome due to a point mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital diaphragmatic hernia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11290732).
• BP6: Variant 15-75372148-G-C is Benign according to our data. Variant chr15-75372148-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2435950.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145358.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIN3A	NM_001145358.2	MANE Select	c.3653C>G	p.Thr1218Ser	missense	Exon 21 of 21	NP_001138830.1	Q96ST3
	SIN3A	NM_001145357.2		c.3653C>G	p.Thr1218Ser	missense	Exon 21 of 21	NP_001138829.1	Q96ST3
	SIN3A	NM_001437462.1		c.3653C>G	p.Thr1218Ser	missense	Exon 22 of 22	NP_001424391.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIN3A	ENST00000394947.8	TSL:1 MANE Select	c.3653C>G	p.Thr1218Ser	missense	Exon 21 of 21	ENSP00000378402.3	Q96ST3
	SIN3A	ENST00000360439.8	TSL:1	c.3653C>G	p.Thr1218Ser	missense	Exon 21 of 21	ENSP00000353622.4	Q96ST3
	SIN3A	ENST00000394949.8	TSL:1	c.3653C>G	p.Thr1218Ser	missense	Exon 21 of 21	ENSP00000378403.4	Q96ST3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	SIN3A-related intellectual disability syndrome due to a point mutation (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.042
Sift	Benign	0.77	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.099
MutPred		0.39		Loss of phosphorylation at T1218 (P = 0.0347)
MVP		0.46
MPC		0.58
ClinPred		0.38	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.028
gMVP		0.63

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

hg19: chr15-75664489;