chr6-65405388-G-GAAAA

Variant names:

• chr6-65405388-G-GAAAA
• rs34154043
• NM_001142800.2:c.863-25_863-22dupTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001142800.2(EYS):​c.863-25_863-22dupTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,472,026 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0070 (3 hom.)
• Consequence: EYS NM_001142800.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.391
• Publications: 4 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]

EYS Gene-Disease associations (from GenCC):

• EYS-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• retinitis pigmentosa 25

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.863-25_863-22dupTTTT		intron_variant	Intron 5 of 42	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.863-25_863-22dupTTTT		intron_variant	Intron 5 of 43		NP_001278938.1
EYS	NM_001142801.2	c.863-25_863-22dupTTTT		intron_variant	Intron 5 of 11		NP_001136273.1
EYS	NM_198283.2	c.863-25_863-22dupTTTT		intron_variant	Intron 4 of 9		NP_938024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.863-22_863-21insTTTT		intron_variant	Intron 5 of 42	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.863-22_863-21insTTTT		intron_variant	Intron 5 of 43	1		ENSP00000359655.3
EYS	ENST00000393380.6	c.863-22_863-21insTTTT		intron_variant	Intron 5 of 11	1		ENSP00000377042.2
EYS	ENST00000342421.9	c.863-22_863-21insTTTT		intron_variant	Intron 3 of 8	1		ENSP00000341818.5

Frequencies

GnomAD3 genomes AF: 0.000216 AC: 32 AN: 148256 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000202

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.000105

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000299

Gnomad OTH AF: 0.000490

GnomAD2 exomes AF: 0.00356 AC: 722 AN: 202572 AF XY: 0.00337

Gnomad AFR exome AF: 0.000220

Gnomad AMR exome AF: 0.00482

Gnomad ASJ exome AF: 0.00475

Gnomad EAS exome AF: 0.00284

Gnomad FIN exome AF: 0.00363

Gnomad NFE exome AF: 0.00396

Gnomad OTH exome AF: 0.00403

GnomAD4 exome AF: 0.00695 AC: 9206 AN: 1323668 Hom.: 3 Cov.: 25 AF XY: 0.00678 AC XY: 4492 AN XY: 662142

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000899 AC: 27 AN: 30044

American (AMR) AF: 0.00467 AC: 177 AN: 37862

Ashkenazi Jewish (ASJ) AF: 0.00570 AC: 136 AN: 23840

East Asian (EAS) AF: 0.00304 AC: 114 AN: 37538

South Asian (SAS) AF: 0.00277 AC: 212 AN: 76556

European-Finnish (FIN) AF: 0.00409 AC: 207 AN: 50630

Middle Eastern (MID) AF: 0.00830 AC: 44 AN: 5300

European-Non Finnish (NFE) AF: 0.00791 AC: 7968 AN: 1006916

Other (OTH) AF: 0.00584 AC: 321 AN: 54982

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000216 AC: 32 AN: 148358 Hom.: 0 Cov.: 0 AF XY: 0.000152 AC XY: 11 AN XY: 72232

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000988 AC: 4 AN: 40502

American (AMR) AF: 0.000202 AC: 3 AN: 14886

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5040

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4726

European-Finnish (FIN) AF: 0.000105 AC: 1 AN: 9528

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000299 AC: 20 AN: 66978

Other (OTH) AF: 0.000486 AC: 1 AN: 2058

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00571 Hom.: 270

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34154043; hg19: chr6-66115281;