rs879255618

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr15-75411696-TG-T
• chr15-75411696-TG-TGG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000394947.8(SIN3A):​c.803delC​(p.Pro268HisfsTer19) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,460,550 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SIN3A ENST00000394947.8 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.44
• 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: Illumina, G2P, ClinGen
• chromosome 15q24 deletion syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000394947.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIN3A	NM_001145358.2	MANE Select	c.803delC	p.Pro268HisfsTer19	frameshift	Exon 6 of 21	NP_001138830.1
	SIN3A	NM_001145357.2		c.803delC	p.Pro268HisfsTer19	frameshift	Exon 6 of 21	NP_001138829.1
	SIN3A	NM_001437462.1		c.803delC	p.Pro268HisfsTer19	frameshift	Exon 7 of 22	NP_001424391.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIN3A	ENST00000394947.8	TSL:1 MANE Select	c.803delC	p.Pro268HisfsTer19	frameshift	Exon 6 of 21	ENSP00000378402.3
	SIN3A	ENST00000360439.8	TSL:1	c.803delC	p.Pro268HisfsTer19	frameshift	Exon 6 of 21	ENSP00000353622.4
	SIN3A	ENST00000394949.8	TSL:1	c.803delC	p.Pro268HisfsTer19	frameshift	Exon 6 of 21	ENSP00000378403.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460550 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726392

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111016

Other (OTH) AF: 0.00 AC: 0 AN: 60350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4

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;