chr5-74636069-G-C

Position:

• chr5-74636069-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003633.4(ENC1):​c.417C>G​(p.Phe139Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENC1 NM_003633.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.26

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]

ENC1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENC1	NM_003633.4	c.417C>G	p.Phe139Leu	missense_variant	2/3	ENST00000302351.9	NP_003624.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENC1	ENST00000302351.9	c.417C>G	p.Phe139Leu	missense_variant	2/3	1	NM_003633.4	ENSP00000306356.4
ENC1	ENST00000618628.4	c.417C>G	p.Phe139Leu	missense_variant	3/4	5		ENSP00000479101.1
ENC1	ENST00000651128.1	c.417C>G	p.Phe139Leu	missense_variant	3/4			ENSP00000499185.1
ENC1	ENST00000510316.5	c.198C>G	p.Phe66Leu	missense_variant	2/3	2		ENSP00000423804.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

ENC1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

The ENC1 c.417C>G variant is predicted to result in the amino acid substitution p.Phe139Leu. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;D;.;D
Eigen	Benign	0.097
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	.;D;D;.
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.0055	D
MutationAssessor	Uncertain	2.7	M;M;.;M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.2	D;.;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0040	D;.;D;D
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		0.85	P;P;.;P
Vest4		0.93
MutPred		0.83		Loss of ubiquitination at K142 (P = 0.1166);Loss of ubiquitination at K142 (P = 0.1166);.;Loss of ubiquitination at K142 (P = 0.1166);
MVP		0.78
MPC		1.2
ClinPred		0.99	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75

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: chr5-73931894;