11-64314039-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_004451.5(ESRRA):​c.414G>C​(p.Lys138Asn) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ESRRA
NM_004451.5 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83
Variant links:
Genes affected
ESRRA (HGNC:3471): (estrogen related receptor alpha) The protein encoded by this gene is a nuclear receptor that is most closely related to the estrogen receptor. This protein acts as a site-specific transcription factor and interacts with members of the PGC-1 family of transcription cofactors to regulate the expression of most genes involved in cellular energy production as well as in the process of mitochondrial biogenesis. A processed pseudogene of ESRRA is located on chromosome 13q12.1. [provided by RefSeq, Jun 2019]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a mutagenesis_site Abolishes acetylation by PCAF/KAT2B; when associated with R-129, R-160 and R-162. (size 0) in uniprot entity ERR1_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ESRRANM_004451.5 linkuse as main transcriptc.414G>C p.Lys138Asn missense_variant 3/7 ENST00000000442.11 NP_004442.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ESRRAENST00000000442.11 linkuse as main transcriptc.414G>C p.Lys138Asn missense_variant 3/71 NM_004451.5 ENSP00000000442 P4P11474-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 14, 2023The c.414G>C (p.K138N) alteration is located in exon 3 (coding exon 2) of the ESRRA gene. This alteration results from a G to C substitution at nucleotide position 414, causing the lysine (K) at amino acid position 138 to be replaced by an asparagine (N). 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
1.0
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
.;D;D
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.97
D;.;D
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.93
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.2
M;M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Uncertain
-4.2
D;D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0010
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.90
MutPred
0.77
Loss of methylation at K138 (P = 2e-04);Loss of methylation at K138 (P = 2e-04);Loss of methylation at K138 (P = 2e-04);
MVP
0.96
MPC
1.7
ClinPred
1.0
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.81
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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: chr11-64081511; API