11-125581279-C-T

Position:

• chr11-125581279-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_004879.5(EI24):​c.742C>T​(p.Pro248Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EI24 NM_004879.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.35

Genes affected

EI24 (HGNC:13276): (EI24 autophagy associated transmembrane protein) This gene encodes a putative tumor suppressor and has higher expression in p53-expressing cells than in control cells and is an immediate-early induction target of p53-mediated apoptosis. The encoded protein may suppress cell growth by inducing apoptotic cell death through the caspase 9 and mitochondrial pathways. This gene is located on human chromosome 11q24, a region frequently altered in cancers. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene have been defined on chromosomes 1, 3, 7, and 8. [provided by RefSeq, Feb 2014]

STT3A-AS1 (HGNC:):

FEZ1 (HGNC:3659): (fasciculation and elongation protein zeta 1) This gene is an ortholog of the C. elegans unc-76 gene, which is necessary for normal axonal bundling and elongation within axon bundles. Expression of this gene in C. elegans unc-76 mutants can restore to the mutants partial locomotion and axonal fasciculation, suggesting that it also functions in axonal outgrowth. The N-terminal half of the gene product is highly acidic. Alternatively spliced transcript variants encoding different isoforms of this protein have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 11-125581279-C-T is Pathogenic according to our data. Variant chr11-125581279-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 996579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-125581279-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EI24	NM_004879.5	c.742C>T	p.Pro248Ser	missense_variant	9/11	ENST00000278903.11
STT3A-AS1	NR_132372.1	n.152-7705G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EI24	ENST00000278903.11	c.742C>T	p.Pro248Ser	missense_variant	9/11	1	NM_004879.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;.;T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;.;D;D;T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.8	M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Pathogenic	-6.5	D;.;.;.;.
REVEL	Pathogenic	0.75
Sift	Benign	0.032	D;.;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		0.043	B;.;.;.;B
Vest4		0.92
MutPred		0.78		Gain of catalytic residue at P248 (P = 0.0029);.;.;.;Gain of catalytic residue at P248 (P = 0.0029);
MVP		0.49
MPC		0.48
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.43
gMVP		0.86

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: rs1938981293; hg19: chr11-125451175;