chr14-76491731-G-A

Variant names:

• chr14-76491731-G-A
• rs754237725
• NM_001379180.1:c.1120+15G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001379180.1(ESRRB):​c.1120+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000505 in 1,563,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: ESRRB NM_001379180.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00300
• 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: PanelApp Australia, G2P, Ambry Genetics, 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-76491731-G-A is Benign according to our data. Variant chr14-76491731-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000524 (74/1411522) while in subpopulation AMR AF = 0.000221 (8/36226). AF 95% confidence interval is 0.00011. There are 0 homozygotes in GnomAdExome4. There are 45 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRB	NM_001379180.1	c.1120+15G>A		intron_variant	Intron 6 of 6	ENST00000644823.1	NP_001366109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESRRB	ENST00000644823.1	c.1120+15G>A		intron_variant	Intron 6 of 6		NM_001379180.1	ENSP00000493776.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152260 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000410 AC: 7 AN: 170660 AF XY: 0.0000331

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000145

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000524 AC: 74 AN: 1411522 Hom.: 0 Cov.: 35 AF XY: 0.0000646 AC XY: 45 AN XY: 697104

African (AFR) AF: 0.0000304 AC: 1 AN: 32922

American (AMR) AF: 0.000221 AC: 8 AN: 36226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25094

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38172

South Asian (SAS) AF: 0.0000250 AC: 2 AN: 80058

European-Finnish (FIN) AF: 0.0000201 AC: 1 AN: 49760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4182

European-Non Finnish (NFE) AF: 0.0000561 AC: 61 AN: 1086620

Other (OTH) AF: 0.00 AC: 0 AN: 58488

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152260 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 31, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.1057+15G>A in intron 8 of ESRRB: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. -

not provided Benign:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.0
DANN	Benign	0.89
PhyloP100		-0.0030

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

Other links and lift over

dbSNP: rs754237725; hg19: chr14-76958074;