rs111991705

Variant names:

• chr6-63721609-C-T
• rs111991705
• NM_001142800.2:c.8422G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-63721609-C-T
• chr6-63721609-C-G

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.8422G>A​(p.Ala2808Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,551,202 control chromosomes in the GnomAD database, including 64 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2808V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0070 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (49 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.408
• Publications: 9 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=0.0044193566).
• BP6: Variant 6-63721609-C-T is Benign according to our data. Variant chr6-63721609-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252538.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00702 (1068/152162) while in subpopulation SAS AF = 0.0235 (113/4816). AF 95% confidence interval is 0.02. There are 15 homozygotes in GnomAd4. There are 550 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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.8422G>A	p.Ala2808Thr	missense	Exon 43 of 43	NP_001136272.1	Q5T1H1-1
	PHF3	NM_001370348.2	MANE Select	c.*7901C>T		3_prime_UTR	Exon 16 of 16	NP_001357277.1	Q92576-1
	EYS	NM_001292009.2		c.8485G>A	p.Ala2829Thr	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.8422G>A	p.Ala2808Thr	missense	Exon 43 of 43	ENSP00000424243.1	Q5T1H1-1
	EYS	ENST00000370621.7	TSL:1	c.8485G>A	p.Ala2829Thr	missense	Exon 44 of 44	ENSP00000359655.3	Q5T1H1-3
	PHF3	ENST00000262043.8	TSL:5 MANE Select	c.*7901C>T		3_prime_UTR	Exon 16 of 16	ENSP00000262043.4	Q92576-1

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 1066 AN: 152044 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00847

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00510 AC: 802 AN: 157312 AF XY: 0.00591

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00176

Gnomad EAS exome AF: 0.0109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000164

Gnomad OTH exome AF: 0.00316

GnomAD4 exome AF: 0.00200 AC: 2792 AN: 1399040 Hom.: 49 Cov.: 31 AF XY: 0.00247 AC XY: 1702 AN XY: 690046

African (AFR) AF: 0.0209 AC: 661 AN: 31574

American (AMR) AF: 0.00148 AC: 53 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00139 AC: 35 AN: 25174

East Asian (EAS) AF: 0.00481 AC: 172 AN: 35724

South Asian (SAS) AF: 0.0197 AC: 1564 AN: 79222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49358

Middle Eastern (MID) AF: 0.00474 AC: 27 AN: 5700

European-Non Finnish (NFE) AF: 0.0000723 AC: 78 AN: 1078538

Other (OTH) AF: 0.00348 AC: 202 AN: 58046

GnomAD4 genome AF: 0.00702 AC: 1068 AN: 152162 Hom.: 15 Cov.: 32 AF XY: 0.00739 AC XY: 550 AN XY: 74382

African (AFR) AF: 0.0205 AC: 853 AN: 41538

American (AMR) AF: 0.00223 AC: 34 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00849 AC: 44 AN: 5182

South Asian (SAS) AF: 0.0235 AC: 113 AN: 4816

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67984

Other (OTH) AF: 0.00285 AC: 6 AN: 2106

Alfa AF: 0.00284 Hom.: 11

Bravo AF: 0.00720

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0210 AC: 29

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.00890 AC: 222

Asia WGS AF: 0.0180 AC: 63 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.41
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.14
Sift	Uncertain	0.027	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.59	P
Vest4		0.36
MVP		0.34
MPC		0.010
ClinPred		0.0061	T
GERP RS		2.9
Varity_R		0.038
gMVP		0.27
Mutation Taster		=97/3	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: rs111991705; hg19: chr6-64431505;