chr6-63720604-C-A

Variant names:

• chr6-63720604-C-A
• rs1038659994
• NM_001142800.2:c.9427G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001142800.2(EYS):​c.9427G>T​(p.Val3143Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,324,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.629

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain Laminin G-like 5 (size 190) in uniprot entity EYS_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_001142800.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071231365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.9427G>T	p.Val3143Phe	missense_variant	Exon 43 of 43	ENST00000503581.6	NP_001136272.1
PHF3	NM_001370348.2	c.*6896C>A		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.9427G>T	p.Val3143Phe	missense_variant	Exon 43 of 43	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.9490G>T	p.Val3164Phe	missense_variant	Exon 44 of 44	1		ENSP00000359655.3
PHF3	ENST00000262043.8	c.*6896C>A		3_prime_UTR_variant	Exon 16 of 16	5	NM_001370348.2	ENSP00000262043.4
PHF3	ENST00000505138.1	c.361+9242C>A		intron_variant	Intron 3 of 4	3		ENSP00000421417.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1324566 Hom.: 0 Cov.: 28 AF XY: 0.00000154 AC XY: 1 AN XY: 648114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000192

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.042	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.47	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.071	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	.;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.017	B;B
Vest4		0.24
MutPred		0.13		.;Gain of solvent accessibility (P = 0.1185);
MVP		0.14
MPC		0.014
ClinPred		0.078	T
GERP RS		-3.5
Varity_R		0.19
gMVP		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: rs1038659994; hg19: chr6-64430500; COSMIC: COSV65502873;