chr19-47834415-T-A

Variant names:

• chr19-47834415-T-A
• rs1568624071
• NM_000554.6:c.-29T>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_000554.6(CRX):​c.-29T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CRX NM_000554.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.77
• Publications: 0 publications found

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]

CRX Gene-Disease associations (from GenCC):

• cone-rod dystrophy 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary macular dystrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Leber congenital amaurosis 7

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-47834415-T-A is Benign according to our data. Variant chr19-47834415-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 618048.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRX	NM_000554.6	c.-29T>A		5_prime_UTR_variant	Exon 2 of 4	ENST00000221996.12	NP_000545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRX	ENST00000221996.12	c.-29T>A		5_prime_UTR_variant	Exon 2 of 4	2	NM_000554.6	ENSP00000221996.5
CRX	ENST00000556527.1	n.78-1828T>A		intron_variant	Intron 1 of 1	1
CRX	ENST00000566686.5	c.-29T>A		5_prime_UTR_variant	Exon 2 of 3	5		ENSP00000457808.2
CRX	ENST00000613299.1	c.-29T>A		5_prime_UTR_variant	Exon 2 of 3	3		ENSP00000478106.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 29, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CRX c.-29T>A variant, to our knowledge, is not reported in the medical literature or in gene-specific databases. This variant is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This is a 5'UTR variant, the nucleotide at this position is not well conserved, and computational algorithms predict no change (Alamut v.2.11). Additionally, ARUP has detected this variant in an individual with an alternative molecular basis for disease. Considering available information, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.0
DANN	Benign	0.93
PhyloP100		-1.8

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: rs1568624071; hg19: chr19-48337672;