8-71198118-T-G

Position:

• chr8-71198118-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000503.6(EYA1):​c.*1222A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 151,630 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (33 hom., cov: 32)
  • Exomes 𝑓: 0.011 (0 hom.)
• Consequence: EYA1 NM_000503.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.00

Genes affected

EYA1 (HGNC:3519): (EYA transcriptional coactivator and phosphatase 1) This gene encodes a member of the eyes absent (EYA) family of proteins. The encoded protein may play a role in the developing kidney, branchial arches, eye, and ear. Mutations of this gene have been associated with branchiootorenal dysplasia syndrome, branchiootic syndrome, and sporadic cases of congenital cataracts and ocular anterior segment anomalies. A similar protein in mice can act as a transcriptional activator. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2013]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 8-71198118-T-G is Benign according to our data. Variant chr8-71198118-T-G is described in ClinVar as [Benign]. Clinvar id is 363632.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0139 (2110/151366) while in subpopulation NFE AF= 0.0213 (1449/67988). AF 95% confidence interval is 0.0204. There are 33 homozygotes in gnomad4. There are 991 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA1	NM_000503.6	c.*1222A>C		3_prime_UTR_variant	18/18	ENST00000340726.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA1	ENST00000340726.8	c.*1222A>C		3_prime_UTR_variant	18/18	1	NM_000503.6	P4
	ENST00000521685.5	n.271-1022T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2115 AN: 151256 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.0347

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.00833

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0145

GnomAD4 exome AF: 0.0114 AC: 3 AN: 264 Hom.: 0 Cov.: 0 AF XY: 0.0119 AC XY: 2 AN XY: 168

Gnomad4 FIN exome AF: 0.0115

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0139 AC: 2110 AN: 151366 Hom.: 33 Cov.: 32 AF XY: 0.0134 AC XY: 991 AN XY: 73982

Gnomad4 AFR AF: 0.00417

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.0347

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.00833

Gnomad4 NFE AF: 0.0213

Gnomad4 OTH AF: 0.0144

Alfa AF: 0.0172 Hom.: 3

Bravo AF: 0.0136

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Branchiootic syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Otofaciocervical syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.4
DANN	Benign	0.70

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: rs117394899; hg19: chr8-72110353;