chr12-55721144-C-T

Variant names:

• chr12-55721144-C-T
• rs201563497
• NM_002905.5:c.-32-9C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001199771.3(RDH5):​c.-37-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,602,212 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (7 hom.)
• Consequence: RDH5 NM_001199771.3 splice_region, intron
• Scores: Splicing: ADA: 0.006331
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0160

Genes affected

RDH5 (HGNC:9940): (retinol dehydrogenase 5) This gene encodes an enzyme belonging to the short-chain dehydrogenases/reductases (SDR) family. This retinol dehydrogenase functions to catalyze the final step in the biosynthesis of 11-cis retinaldehyde, which is the universal chromophore of visual pigments. Mutations in this gene cause autosomal recessive fundus albipunctatus, a rare form of night blindness that is characterized by a delay in the regeneration of cone and rod photopigments. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring upstream BLOC1S1 (biogenesis of lysosomal organelles complex-1, subunit 1) gene. [provided by RefSeq, Dec 2010]

ENSG00000258311 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 12-55721144-C-T is Benign according to our data. Variant chr12-55721144-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 386306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00457 (696/152300) while in subpopulation AFR AF = 0.0161 (668/41570). AF 95% confidence interval is 0.0151. There are 4 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDH5	NM_002905.5	c.-32-9C>T		intron_variant	Intron 1 of 4	ENST00000257895.10	NP_002896.2
RDH5	NM_001199771.3	c.-37-4C>T		splice_region_variant, intron_variant	Intron 1 of 4		NP_001186700.1
BLOC1S1-RDH5	NR_037658.1	n.370-545C>T		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDH5	ENST00000257895.10	c.-32-9C>T		intron_variant	Intron 1 of 4	1	NM_002905.5	ENSP00000257895.6
ENSG00000258311	ENST00000550412.5	c.352-545C>T		intron_variant	Intron 3 of 3	2		ENSP00000447650.1

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 696 AN: 152182 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00128 AC: 317 AN: 247364 AF XY: 0.00109

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000483 AC: 700 AN: 1449912 Hom.: 7 Cov.: 30 AF XY: 0.000420 AC XY: 303 AN XY: 721912

Gnomad4 AFR exome AF: 0.0179 AC: 595 AN: 33254

Gnomad4 AMR exome AF: 0.00112 AC: 50 AN: 44704

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26074

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39610

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 85960

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52898

Gnomad4 NFE exome AF: 0.00000544 AC: 6 AN: 1102278

Gnomad4 Remaining exome AF: 0.000801 AC: 48 AN: 59950

GnomAD4 genome AF: 0.00457 AC: 696 AN: 152300 Hom.: 4 Cov.: 32 AF XY: 0.00431 AC XY: 321 AN XY: 74470

Gnomad4 AFR AF: 0.0161 AC: 0.0160693 AN: 0.0160693

Gnomad4 AMR AF: 0.00157 AC: 0.00156904 AN: 0.00156904

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000147011 AN: 0.0000147011

Gnomad4 OTH AF: 0.00142 AC: 0.00141911 AN: 0.00141911

Alfa AF: 0.00320 Hom.: 0

Bravo AF: 0.00522

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

May 13, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Pigmentary retinal dystrophy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.87
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0063
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 23

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

Publications

LitVar

Other links and lift over

dbSNP: rs201563497; hg19: chr12-56114928;