chr11-64307277-C-T

Position:

• chr11-64307277-C-T

Variant summary

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

The NM_004451.5(ESRRA):​c.98C>T​(p.Pro33Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ESRRA NM_004451.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.396

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]

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=0.25997305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESRRA	NM_004451.5	c.98C>T	p.Pro33Leu	missense_variant	2/7	ENST00000000442.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESRRA	ENST00000000442.11	c.98C>T	p.Pro33Leu	missense_variant	2/7	1	NM_004451.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 01, 2022

The c.98C>T (p.P33L) alteration is located in exon 2 (coding exon 1) of the ESRRA gene. This alteration results from a C to T substitution at nucleotide position 98, causing the proline (P) at amino acid position 33 to be replaced by a leucine (L). 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	0.076
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T;T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.88	D;.;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	0.55	N;N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N;N;N;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.022	D;D;D;D
Sift4G	Benign	0.067	T;T;T;T
Polyphen		0.55	P;P;P;.
Vest4		0.25
MutPred		0.29		Loss of glycosylation at P33 (P = 0.0315);Loss of glycosylation at P33 (P = 0.0315);Loss of glycosylation at P33 (P = 0.0315);Loss of glycosylation at P33 (P = 0.0315);
MVP		0.82
MPC		0.95
ClinPred		0.60	D
GERP RS		4.3
Varity_R		0.093
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs768541509; hg19: chr11-64074749;