chr14-76439754-C-T

Variant names:

• chr14-76439754-C-T
• rs727503040
• NM_001379180.1:c.460+4C>T

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		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.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ESRRB NM_001379180.1	MANE Select	c.460+4C>T	splice_regionintron	Intron 2 of 6	Prot: NP_001366109.1 UniProt:
	ESRRB NM_004452.4		c.397+4C>T	splice_regionintron	Intron 4 of 10	Prot: NP_004443.3
	ESRRB NM_001411038.1		c.412+4C>T	splice_regionintron	Intron 2 of 6	Prot: NP_001397967.1 UniProt:

ESRRB NM_001379180.1

MANE Select

HGVSc / HGVSpc.460+4C>T

Exon rankIntron 2 of 6

splice_regionintron

Prot: NP_001366109.1UniProt: A0A2R8Y491

ESRRB NM_004452.4

HGVSc / HGVSpc.397+4C>T

Exon rankIntron 4 of 10

splice_regionintron

Prot: NP_004443.3

ESRRB NM_001411038.1

HGVSc / HGVSpc.412+4C>T

Exon rankIntron 2 of 6

splice_regionintron

Prot: NP_001397967.1UniProt: E7EWD9

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ESRRB ENST00000644823.1	MANE Select	c.460+4C>T	splice_regionintron	Intron 2 of 6	Prot: ENSP00000493776.1 UniProt:
	ESRRB ENST00000509242.5	TSL:1	c.397+4C>T	splice_regionintron	Intron 2 of 8	Prot: ENSP00000422488.1 UniProt:
	ESRRB ENST00000505752.6	TSL:1	n.397+4C>T	splice_regionintron	Intron 4 of 11	Prot: ENSP00000423004.1 UniProt:

ESRRB ENST00000644823.1

MANE Select

HGVSc / HGVSpc.460+4C>T

Exon rankIntron 2 of 6

splice_regionintron

Prot: ENSP00000493776.1UniProt: A0A2R8Y491

ESRRB ENST00000509242.5

TSL:1

HGVSc / HGVSpc.397+4C>T

Exon rankIntron 2 of 8

splice_regionintron

Prot: ENSP00000422488.1UniProt: O95718-1

ESRRB ENST00000505752.6

TSL:1

HGVSc / HGVSpn.397+4C>T

Exon rankIntron 4 of 11

splice_regionintron

Prot: ENSP00000423004.1UniProt: 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	AF:	AC:	Hom:	AN:	Cov:33
GnomAD2 exomes	AF: 0.0000361	AC:9	Hom:	AN:249550	Cov:
GnomAD4 exome	AF: 0.0000219	AC:32	Hom:0	AN:1460138	Cov:36
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
TOPMed (Bravo)	AF: 0.0000302	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000774	AC:2	Hom:0	AN:25828	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
Turkish Variome	AF: 0.000358	AC:2	Hom:0	AN:5106	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	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

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
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	-0.078	Neutral

Showing 8 of 8 scores

Splicing Scores

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

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs727503040;

hg19: chr14-76906097;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar