rs758975335

Variant names:

• chr19-11507515-C-T
• rs758975335
• ENST00000252440.11:c.844G>A

Variant summary

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

The NM_001142464.3(ECSIT):​c.844G>A​(p.Ala282Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ECSIT NM_001142464.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.222
• Publications: 2 publications found

Genes affected

ECSIT (HGNC:29548): (ECSIT signaling integrator) Predicted to enable DNA-binding transcription factor activity and chromatin binding activity. Involved in regulation of oxidoreductase activity and regulation of protein complex stability. Located in cytosol; mitochondrion; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.16664678).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142464.3. 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
	ECSIT	NM_016581.5	MANE Select	c.993G>A	p.Gln331Gln	synonymous	Exon 7 of 8	NP_057665.2
	ECSIT	NM_001142464.3		c.844G>A	p.Ala282Thr	missense	Exon 6 of 7	NP_001135936.1	Q9BQ95-2
	ECSIT	NM_001243204.2		c.872G>A	p.Ser291Asn	missense	Exon 7 of 8	NP_001230133.1	Q9BQ95-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECSIT	ENST00000252440.11	TSL:1	c.844G>A	p.Ala282Thr	missense	Exon 6 of 7	ENSP00000252440.6	Q9BQ95-2
	ECSIT	ENST00000591104.5	TSL:1	c.872G>A	p.Ser291Asn	missense	Exon 7 of 8	ENSP00000466559.1	Q9BQ95-4
	ECSIT	ENST00000270517.12	TSL:1 MANE Select	c.993G>A	p.Gln331Gln	synonymous	Exon 7 of 8	ENSP00000270517.6	Q9BQ95-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251474 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74298

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

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	4.3
DANN	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.22
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.14
Sift	Benign	0.16	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.28
MutPred		0.17		Gain of phosphorylation at A282 (P = 0.0424)
MVP		0.46
ClinPred		0.16	T
GERP RS		4.8
Mutation Taster		=90/10	polymorphism

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: rs758975335; hg19: chr19-11618330;