chr15-75371996-C-T

Variant names:

• chr15-75371996-C-T
• NM_001145358.2:c.3805G>A

Variant summary

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

The NM_001145358.2(SIN3A):​c.3805G>A​(p.Val1269Ile) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIN3A NM_001145358.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07295427).

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.3805G>A	p.Val1269Ile	missense	Exon 21 of 21	NP_001138830.1	Q96ST3
	SIN3A	NM_001145357.2		c.3805G>A	p.Val1269Ile	missense	Exon 21 of 21	NP_001138829.1	Q96ST3
	SIN3A	NM_001437462.1		c.3805G>A	p.Val1269Ile	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.3805G>A	p.Val1269Ile	missense	Exon 21 of 21	ENSP00000378402.3	Q96ST3
	SIN3A	ENST00000360439.8	TSL:1	c.3805G>A	p.Val1269Ile	missense	Exon 21 of 21	ENSP00000353622.4	Q96ST3
	SIN3A	ENST00000394949.8	TSL:1	c.3805G>A	p.Val1269Ile	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	Benign	0.068
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.0051
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.0
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.13
Sift	Benign	0.39	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.012
MutPred		0.21		Loss of sheet (P = 0.0817)
MVP		0.19
MPC		0.52
ClinPred		0.51	D
GERP RS		4.0
Varity_R		0.024
gMVP		0.24

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: chr15-75664337;