NM_001379180.1:c.460+4C>T

Variant names:

Variant summary

Our verdict is The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_ModerateBP6_Moderate

The NM_001379180.1(ESRRB):c.460+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000219 (AC=32) in the gnomAD database across 1,460,138 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000341. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

ESRRB
NM_001379180.1 splice_region, intron

Scores

Splicing: ADA: 0.002958

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.398

Publications

0 publications found

Variant links:

Genes affected

ESRRB (HGNC:3473): (estrogen related receptor beta) This gene encodes a protein with similarity to the estrogen receptor. Its function is unknown; however, a similar protein in mouse plays an essential role in placental development. [provided by RefSeq, Jul 2008]

ESRRB Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 35
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ESRRB links:

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new If you want to explore the variant's impact on the transcript NM_001379180.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 points.

PM2

Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000341 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001379180.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ESRRB	NM_001379180.1	MANE Select	c.460+4C>T	splice_region intron	N/A	NP_001366109.1	A0A2R8Y491
ESRRB	NM_004452.4		c.397+4C>T	splice_region intron	N/A	NP_004443.3
ESRRB	NM_001411038.1		c.412+4C>T	splice_region intron	N/A	NP_001397967.1	E7EWD9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ESRRB	ENST00000644823.1	MANE Select	c.460+4C>T	splice_region intron	N/A	ENSP00000493776.1	A0A2R8Y491
ESRRB	ENST00000509242.5	TSL:1	c.397+4C>T	splice_region intron	N/A	ENSP00000422488.1	O95718-1
ESRRB	ENST00000505752.6	TSL:1	n.397+4C>T	splice_region intron	N/A	ENSP00000423004.1	O95718-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes					33
GnomAD2 exomes	0.0000361	9		249550
GnomAD4 exome	0.0000219	32	0	1460138	36
GnomAD4 genome					33
TOPMed (Bravo)	0.0000302
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.0000774	2	0	25828
Local & regional cohorts 1 source Population-specific and national genomic databases
Turkish Variome	0.000358	2	0	5106

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
Cohort	AF	AC	AN	AF	AC	AN
BipEx (Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
SCHEMA (Schizophrenia)	0.0000691	7	101310	0.0000717	13	181314

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Benign	-	1.7
BayesDel_noAF	Benign	-	-0.41
CADD	Benign	-	16
DANN	Benign	-	0.85
GPN-Star LLR	N/A	-	-2.7
GPN-Star score	N/A	-	2.7
PhyloP100	Benign	-	-0.40
PromoterAI	N/A	Neutral	-0.078

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
dbscSNV1_ADA	Benign	-	0.0030
dbscSNV1_RF	Benign	-	0.038
Pangolin (max)	Benign	-	0.020
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.020

Showing 4 of 4 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Case/control cohorts

ClinVar

Computational Scores

Splicing Scores

Publications

Other links and lift over