8-94646179-A-G

Variant names:

• chr8-94646179-A-G
• rs76736071
• NM_017697.4:c.387A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017697.4(ESRP1):​c.387A>G​(p.Leu129Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,604,072 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (85 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (62 hom.)
• Consequence: ESRP1 NM_017697.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.36
• Publications: 2 publications found

Genes affected

ESRP1 (HGNC:25966): (epithelial splicing regulatory protein 1) ESPR1 is an epithelial cell-type-specific splicing regulator (Warzecha et al., 2009 [PubMed 19285943]).[supplied by OMIM, Aug 2009]

ESRP1 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• hearing loss, autosomal recessive 109

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 8-94646179-A-G is Benign according to our data. Variant chr8-94646179-A-G is described in ClinVar as Benign. ClinVar VariationId is 785258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0581 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017697.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRP1	NM_017697.4	MANE Select	c.387A>G	p.Leu129Leu	synonymous	Exon 4 of 16	NP_060167.2	Q6NXG1-1
	ESRP1	NM_001034915.3		c.387A>G	p.Leu129Leu	synonymous	Exon 4 of 16	NP_001030087.2	Q6NXG1-3
	ESRP1	NM_001122826.2		c.387A>G	p.Leu129Leu	synonymous	Exon 4 of 15	NP_001116298.1	Q6NXG1-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRP1	ENST00000433389.8	TSL:1 MANE Select	c.387A>G	p.Leu129Leu	synonymous	Exon 4 of 16	ENSP00000405738.2	Q6NXG1-1
	ESRP1	ENST00000358397.9	TSL:1	c.387A>G	p.Leu129Leu	synonymous	Exon 4 of 16	ENSP00000351168.5	Q6NXG1-3
	ESRP1	ENST00000423620.6	TSL:1	c.387A>G	p.Leu129Leu	synonymous	Exon 4 of 15	ENSP00000407349.2	Q6NXG1-5

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2631 AN: 152166 Hom.: 83 Cov.: 33

Gnomad AFR AF: 0.0599

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00430 AC: 1064 AN: 247454 AF XY: 0.00344

Gnomad AFR exome AF: 0.0615

Gnomad AMR exome AF: 0.00244

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00250

GnomAD4 exome AF: 0.00169 AC: 2453 AN: 1451788 Hom.: 62 Cov.: 28 AF XY: 0.00149 AC XY: 1076 AN XY: 722806

African (AFR) AF: 0.0590 AC: 1958 AN: 33198

American (AMR) AF: 0.00322 AC: 143 AN: 44364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.0000701 AC: 6 AN: 85582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00244 AC: 14 AN: 5748

European-Non Finnish (NFE) AF: 0.000108 AC: 119 AN: 1103996

Other (OTH) AF: 0.00355 AC: 213 AN: 59998

GnomAD4 genome AF: 0.0174 AC: 2643 AN: 152284 Hom.: 85 Cov.: 33 AF XY: 0.0171 AC XY: 1273 AN XY: 74476

African (AFR) AF: 0.0601 AC: 2496 AN: 41560

American (AMR) AF: 0.00608 AC: 93 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67996

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.00786 Hom.: 21

Bravo AF: 0.0199

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ESRP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.7
DANN	Benign	0.78
PhyloP100		1.4
PromoterAI		0.061	Neutral
Mutation Taster		=95/5	polymorphism (auto)

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: rs76736071; hg19: chr8-95658407; COSMIC: COSV104421832;