6-63720310-A-T

Variant names:

• chr6-63720310-A-T
• rs553600976
• NM_001142800.2:c.*286T>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001142800.2(EYS):​c.*286T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 391,064 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: EYS NM_001142800.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.557
• Publications: 0 publications found

Genes affected

EYS (HGNC:21555): (eyes shut homolog) The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

PHF3 (HGNC:8921): (PHD finger protein 3) This gene encodes a member of a PHD finger-containing gene family. This gene may function as a transcription factor and may be involved in glioblastomas development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.*286T>A		3_prime_UTR_variant	Exon 43 of 43	ENST00000503581.6	NP_001136272.1
PHF3	NM_001370348.2	c.*6602A>T		3_prime_UTR_variant	Exon 16 of 16	ENST00000262043.8	NP_001357277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.*286T>A		3_prime_UTR_variant	Exon 43 of 43	5	NM_001142800.2	ENSP00000424243.1
PHF3	ENST00000262043.8	c.*6602A>T		3_prime_UTR_variant	Exon 16 of 16	5	NM_001370348.2	ENSP00000262043.4
EYS	ENST00000370621.7	c.*286T>A		3_prime_UTR_variant	Exon 44 of 44	1		ENSP00000359655.3
PHF3	ENST00000505138.1	c.361+8948A>T		intron_variant	Intron 3 of 4	3		ENSP00000421417.1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152106 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00682

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000121 AC: 29 AN: 238840 Hom.: 1 Cov.: 0 AF XY: 0.000149 AC XY: 18 AN XY: 120884

African (AFR) AF: 0.00 AC: 0 AN: 6782

American (AMR) AF: 0.00 AC: 0 AN: 8350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8870

East Asian (EAS) AF: 0.00 AC: 0 AN: 22538

South Asian (SAS) AF: 0.00652 AC: 22 AN: 3376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19504

Middle Eastern (MID) AF: 0.000825 AC: 1 AN: 1212

European-Non Finnish (NFE) AF: 0.0000263 AC: 4 AN: 152370

Other (OTH) AF: 0.000126 AC: 2 AN: 15838

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152224 Hom.: 2 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74436

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00683 AC: 33 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

Asia WGS AF: 0.00464 AC: 16 AN: 3462

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.62
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism

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: rs553600976; hg19: chr6-64430206;