NM_001145358.2:c.3790G>A

Variant names:

• chr15-75372011-C-T
• NM_001145358.2:c.3790G>A

Variant summary

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

The NM_001145358.2(SIN3A):​c.3790G>A​(p.Val1264Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIN3A NM_001145358.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3790G>A	p.Val1264Ile	missense	Exon 21 of 21	NP_001138830.1	Q96ST3
	SIN3A	NM_001145357.2		c.3790G>A	p.Val1264Ile	missense	Exon 21 of 21	NP_001138829.1	Q96ST3
	SIN3A	NM_001437462.1		c.3790G>A	p.Val1264Ile	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.3790G>A	p.Val1264Ile	missense	Exon 21 of 21	ENSP00000378402.3	Q96ST3
	SIN3A	ENST00000360439.8	TSL:1	c.3790G>A	p.Val1264Ile	missense	Exon 21 of 21	ENSP00000353622.4	Q96ST3
	SIN3A	ENST00000394949.8	TSL:1	c.3790G>A	p.Val1264Ile	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: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.25
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.51
MutPred		0.47		Gain of catalytic residue at V1264 (P = 0.0337)
MVP		0.59
MPC		1.1
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.26
gMVP		0.81

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: chr15-75664352;