19-47834486-G-A

Variant summary

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

The NM_000554.6(CRX):c.43G>A(p.Ala15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,888 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A15P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CRX NM_000554.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

Genes affected

CRX (HGNC:2383): (cone-rod homeobox) The protein encoded by this gene is a photoreceptor-specific transcription factor which plays a role in the differentiation of photoreceptor cells. This homeodomain protein is necessary for the maintenance of normal cone and rod function. Mutations in this gene are associated with photoreceptor degeneration, Leber congenital amaurosis type III and the autosomal dominant cone-rod dystrophy 2. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Cone-rod homeobox protein (size 298) in uniprot entity CRX_HUMAN there are 56 pathogenic changes around while only 17 benign (77%) in NM_000554.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1335698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRX	NM_000554.6	c.43G>A	p.Ala15Thr	missense_variant	2/4	ENST00000221996.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRX	ENST00000221996.12	c.43G>A	p.Ala15Thr	missense_variant	2/4	2	NM_000554.6	P1
CRX	ENST00000556527.1	n.78-1757G>A		intron_variant, non_coding_transcript_variant		1
CRX	ENST00000566686.5	c.43G>A	p.Ala15Thr	missense_variant	2/3	5
CRX	ENST00000613299.1	c.43G>A	p.Ala15Thr	missense_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251474 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 10, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 15 of the CRX protein (p.Ala15Thr). This variant is present in population databases (rs559181643, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CRX-related conditions. ClinVar contains an entry for this variant (Variation ID: 1413008). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CRX protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	T;.;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.9	N;N;N;.
Sift	Benign	0.045	D;D;D;.
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.0020	.;B;B;.
Vest4		0.12, 0.13, 0.24
MutPred		0.30		Gain of catalytic residue at A15 (P = 0.0463);Gain of catalytic residue at A15 (P = 0.0463);Gain of catalytic residue at A15 (P = 0.0463);Gain of catalytic residue at A15 (P = 0.0463);
MVP		0.54
MPC		0.17
ClinPred		0.35	T
GERP RS		-0.93
Varity_R		0.056
gMVP		0.60

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: rs559181643; hg19: chr19-48337743; COSMIC: COSV55759295;