14-67678345-G-T

Position:

• chr14-67678345-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000381346.9(RDH11):​c.933C>A​(p.Asp311Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RDH11 ENST00000381346.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22

Genes affected

RDH11 (HGNC:17964): (retinol dehydrogenase 11) Enables NADP-retinol dehydrogenase activity. Involved in cellular detoxification of aldehyde and retinoid metabolic process. Acts upstream of or within retinal metabolic process. Located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

RDH11 (HGNC:):

GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12415519).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH11	NM_016026.4	c.933C>A	p.Asp311Glu	missense_variant	7/7	ENST00000381346.9	NP_057110.3
RDH11	NM_001252650.2	c.723C>A	p.Asp241Glu	missense_variant	6/6		NP_001239579.1
GPHN	XM_047430879.1	c.1313-56850G>T		intron_variant			XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH11	ENST00000381346.9	c.933C>A	p.Asp311Glu	missense_variant	7/7	1	NM_016026.4	ENSP00000370750.4
ENSG00000258466	ENST00000553306.5	n.344+6670C>A		intron_variant		2		ENSP00000450554.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250456 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135498

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461502 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727090

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1377216). This variant has not been reported in the literature in individuals affected with RDH11-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 311 of the RDH11 protein (p.Asp311Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.22	T;.;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.42	T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-1.6	N;.;.;.
MutationTaster	Benign	0.55	N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	1.5	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.78	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.071
MutPred		0.37		Gain of catalytic residue at D311 (P = 0.0716);.;.;.;
MVP		0.82
MPC		0.15
ClinPred		0.14	T
GERP RS		3.4
Varity_R		0.039
gMVP		0.71

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: rs1187309718; hg19: chr14-68145062;