15-75411696-TG-TGG

Variant names:

• chr15-75411696-T-TG
• rs879255618
• NM_001145358.2:c.803dupC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001145358.2(SIN3A):​c.803dupC​(p.Leu269ThrfsTer37) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIN3A NM_001145358.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.44
• Publications: 3 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-75411696-T-TG is Pathogenic according to our data. Variant chr15-75411696-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 253070.Status of the report is no_assertion_criteria_provided, 0 stars.

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.803dupC	p.Leu269ThrfsTer37	frameshift	Exon 6 of 21	NP_001138830.1	Q96ST3
	SIN3A	NM_001145357.2		c.803dupC	p.Leu269ThrfsTer37	frameshift	Exon 6 of 21	NP_001138829.1	Q96ST3
	SIN3A	NM_001437462.1		c.803dupC	p.Leu269ThrfsTer37	frameshift	Exon 7 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.803dupC	p.Leu269ThrfsTer37	frameshift	Exon 6 of 21	ENSP00000378402.3	Q96ST3
	SIN3A	ENST00000360439.8	TSL:1	c.803dupC	p.Leu269ThrfsTer37	frameshift	Exon 6 of 21	ENSP00000353622.4	Q96ST3
	SIN3A	ENST00000394949.8	TSL:1	c.803dupC	p.Leu269ThrfsTer37	frameshift	Exon 6 of 21	ENSP00000378403.4	Q96ST3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs879255618; hg19: chr15-75704037;