rs144513453

Variant names:

• chr6-63721602-G-A
• rs144513453
• NM_001142800.2:c.8429C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001142800.2(EYS):​c.8429C>T​(p.Thr2810Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,551,440 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (2 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.969
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004781574).
• BP6: Variant 6-63721602-G-A is Benign according to our data. Variant chr6-63721602-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287296.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00411 (625/152186) while in subpopulation AFR AF = 0.0135 (562/41524). AF 95% confidence interval is 0.0126. There are 6 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142800.2. 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
	EYS	NM_001142800.2	MANE Select	c.8429C>T	p.Thr2810Ile	missense	Exon 43 of 43	NP_001136272.1	Q5T1H1-1
	PHF3	NM_001370348.2	MANE Select	c.*7894G>A		3_prime_UTR	Exon 16 of 16	NP_001357277.1	Q92576-1
	EYS	NM_001292009.2		c.8492C>T	p.Thr2831Ile	missense	Exon 44 of 44	NP_001278938.1	Q5T1H1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	ENST00000503581.6	TSL:5 MANE Select	c.8429C>T	p.Thr2810Ile	missense	Exon 43 of 43	ENSP00000424243.1	Q5T1H1-1
	EYS	ENST00000370621.7	TSL:1	c.8492C>T	p.Thr2831Ile	missense	Exon 44 of 44	ENSP00000359655.3	Q5T1H1-3
	PHF3	ENST00000262043.8	TSL:5 MANE Select	c.*7894G>A		3_prime_UTR	Exon 16 of 16	ENSP00000262043.4	Q92576-1

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 625 AN: 152068 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.000953 AC: 150 AN: 157414 AF XY: 0.000890

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.000445

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000131

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000509 AC: 712 AN: 1399254 Hom.: 2 Cov.: 31 AF XY: 0.000480 AC XY: 331 AN XY: 690120

African (AFR) AF: 0.0167 AC: 528 AN: 31584

American (AMR) AF: 0.000672 AC: 24 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35724

South Asian (SAS) AF: 0.000164 AC: 13 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49380

Middle Eastern (MID) AF: 0.00438 AC: 25 AN: 5702

European-Non Finnish (NFE) AF: 0.0000426 AC: 46 AN: 1078696

Other (OTH) AF: 0.00129 AC: 75 AN: 58064

GnomAD4 genome AF: 0.00411 AC: 625 AN: 152186 Hom.: 6 Cov.: 32 AF XY: 0.00433 AC XY: 322 AN XY: 74400

African (AFR) AF: 0.0135 AC: 562 AN: 41524

American (AMR) AF: 0.00282 AC: 43 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00202 Hom.: 7

Bravo AF: 0.00459

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00795 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00136 AC: 34

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Retinitis pigmentosa 25 (3)
-	-	2	not specified (2)
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.97
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.078	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.010	B
Vest4		0.070
MVP		0.46
MPC		0.010
ClinPred		0.0052	T
GERP RS		2.8
Varity_R		0.064
gMVP		0.58
Mutation Taster		=75/25	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: rs144513453; hg19: chr6-64431498;