14-67727476-G-T

Position:

• chr14-67727476-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152443.3(RDH12):​c.658+286G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 298,896 control chromosomes in the GnomAD database, including 34,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22581 hom., cov: 28)
  • Exomes 𝑓: 0.48 (12365 hom.)
• Consequence: RDH12 NM_152443.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.298

Genes affected

RDH12 (HGNC:19977): (retinol dehydrogenase 12) The protein encoded by this gene is an NADPH-dependent retinal reductase whose highest activity is toward 9-cis and all-trans-retinol. The encoded enzyme also plays a role in the metabolism of short-chain aldehydes but does not exhibit steroid dehydrogenase activity. Defects in this gene are a cause of Leber congenital amaurosis type 13 and Retinitis Pigmentosa 53. [provided by RefSeq, Sep 2015]

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]

ZFYVE26 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 14-67727476-G-T is Benign according to our data. Variant chr14-67727476-G-T is described in ClinVar as [Benign]. Clinvar id is 1289717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH12	NM_152443.3	c.658+286G>T		intron_variant		ENST00000551171.6	NP_689656.2
GPHN	XM_047430879.1	c.1313-7719G>T		intron_variant			XP_047286835.1
RDH12	XM_047430965.1	c.658+286G>T		intron_variant			XP_047286921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH12	ENST00000551171.6	c.658+286G>T		intron_variant		1	NM_152443.3	ENSP00000449079.1
RDH12	ENST00000267502.3	c.658+286G>T		intron_variant		5		ENSP00000267502.3
ZFYVE26	ENST00000394455.6	n.4032C>A		non_coding_transcript_exon_variant	15/15	2
RDH12	ENST00000552873.1	n.27+286G>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.539 AC: 79034 AN: 146698 Hom.: 22573 Cov.: 28

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.429

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.511

GnomAD4 exome AF: 0.478 AC: 72687 AN: 152118 Hom.: 12365 Cov.: 0 AF XY: 0.467 AC XY: 38572 AN XY: 82592

Gnomad4 AFR exome AF: 0.279

Gnomad4 AMR exome AF: 0.433

Gnomad4 ASJ exome AF: 0.466

Gnomad4 EAS exome AF: 0.439

Gnomad4 SAS exome AF: 0.385

Gnomad4 FIN exome AF: 0.474

Gnomad4 NFE exome AF: 0.523

Gnomad4 OTH exome AF: 0.463

GnomAD4 genome AF: 0.539 AC: 79072 AN: 146778 Hom.: 22581 Cov.: 28 AF XY: 0.533 AC XY: 38017 AN XY: 71364

Gnomad4 AFR AF: 0.342

Gnomad4 AMR AF: 0.550

Gnomad4 ASJ AF: 0.596

Gnomad4 EAS AF: 0.551

Gnomad4 SAS AF: 0.437

Gnomad4 FIN AF: 0.568

Gnomad4 NFE AF: 0.651

Gnomad4 OTH AF: 0.508

Alfa AF: 0.153 Hom.: 442

Bravo AF: 0.529

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.29
DANN	Benign	0.55

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: rs8009179; hg19: chr14-68194193;