19-11508040-C-G

Variant names:

• chr19-11508040-C-G
• rs754850831
• NM_016581.5:c.747G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016581.5(ECSIT):​c.747G>C​(p.Leu249Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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: ECSIT NM_016581.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.407

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10620326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECSIT	NM_016581.5	c.747G>C	p.Leu249Phe	missense_variant	Exon 5 of 8	ENST00000270517.12	NP_057665.2
ECSIT	NM_001142464.3	c.747G>C	p.Leu249Phe	missense_variant	Exon 5 of 7		NP_001135936.1
ECSIT	NM_001243204.2	c.747G>C	p.Leu249Phe	missense_variant	Exon 5 of 8		NP_001230133.1
ECSIT	NM_001142465.3	c.105G>C	p.Leu35Phe	missense_variant	Exon 3 of 6		NP_001135937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECSIT	ENST00000270517.12	c.747G>C	p.Leu249Phe	missense_variant	Exon 5 of 8	1	NM_016581.5	ENSP00000270517.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251490 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.747G>C (p.L249F) alteration is located in exon 5 (coding exon 4) of the ECSIT gene. This alteration results from a G to C substitution at nucleotide position 747, causing the leucine (L) at amino acid position 249 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.37
DANN	Benign	0.64
DEOGEN2	Benign	0.053	T;.;.;.;.;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.70	T;T;T;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.4	M;.;M;.;M;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.35	N;.;N;N;.;.;.
REVEL	Benign	0.15
Sift	Benign	0.70	T;.;T;T;.;.;.
Sift4G	Benign	0.70	T;T;T;T;T;T;.
Polyphen		0.63	P;.;P;.;.;.;.
Vest4		0.28
MutPred		0.54		Gain of methylation at K251 (P = 0.0792);.;Gain of methylation at K251 (P = 0.0792);.;Gain of methylation at K251 (P = 0.0792);.;.;
MVP		0.41
MPC		0.63
ClinPred		0.15	T
GERP RS		-0.43
Varity_R		0.025
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs754850831; hg19: chr19-11618855;