5-74636022-A-T

Position:

• chr5-74636022-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_003633.4(ENC1):​c.464T>A​(p.Leu155Gln) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENC1 NM_003633.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

ENC1 (HGNC:3345): (ectodermal-neural cortex 1) This gene encodes a member of the kelch-related family of actin-binding proteins. The encoded protein plays a role in the oxidative stress response as a regulator of the transcription factor Nrf2, and expression of this gene may play a role in malignant transformation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ENC1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENC1	NM_003633.4	c.464T>A	p.Leu155Gln	missense_variant	2/3	ENST00000302351.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENC1	ENST00000302351.9	c.464T>A	p.Leu155Gln	missense_variant	2/3	1	NM_003633.4	P1
ENC1	ENST00000618628.4	c.464T>A	p.Leu155Gln	missense_variant	3/4	5		P1
ENC1	ENST00000651128.1	c.464T>A	p.Leu155Gln	missense_variant	3/4			P1
ENC1	ENST00000510316.5	c.245T>A	p.Leu82Gln	missense_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.464T>A (p.L155Q) alteration is located in exon 2 (coding exon 1) of the ENC1 gene. This alteration results from a T to A substitution at nucleotide position 464, causing the leucine (L) at amino acid position 155 to be replaced by a glutamine (Q). 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T;.;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.5	M;M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D;.;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.94
MutPred		0.71		Gain of catalytic residue at L155 (P = 0.002);Gain of catalytic residue at L155 (P = 0.002);.;Gain of catalytic residue at L155 (P = 0.002);
MVP		0.83
MPC		2.0
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.82

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-73931847;