chr14-67727376-G-C

Position:

• chr14-67727376-G-C

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+186G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 615,380 control chromosomes in the GnomAD database, including 2,740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (629 hom., cov: 32)
  • Exomes 𝑓: 0.091 (2111 hom.)
• Consequence: RDH12 NM_152443.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.252

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:20761): (zinc finger FYVE-type containing 26) This gene encodes a protein which contains a FYVE zinc finger binding domain. The presence of this domain is thought to target these proteins to membrane lipids through interaction with phospholipids in the membrane. Mutations in this gene are associated with autosomal recessive spastic paraplegia-15. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-67727376-G-C is Benign according to our data. Variant chr14-67727376-G-C is described in ClinVar as [Benign]. Clinvar id is 1257532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH12	NM_152443.3	c.658+186G>C		intron_variant		ENST00000551171.6	NP_689656.2
GPHN	XM_047430879.1	c.1313-7819G>C		intron_variant			XP_047286835.1
RDH12	XM_047430965.1	c.658+186G>C		intron_variant			XP_047286921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH12	ENST00000551171.6	c.658+186G>C		intron_variant		1	NM_152443.3	ENSP00000449079.1
RDH12	ENST00000267502.3	c.658+186G>C		intron_variant		5		ENSP00000267502.3
ZFYVE26	ENST00000394455.6	n.4132C>G		splice_region_variant, non_coding_transcript_exon_variant	15/15	2
RDH12	ENST00000552873.1	n.27+186G>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0896 AC: 13619 AN: 151976 Hom.: 627 Cov.: 32

Gnomad AFR AF: 0.0953

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0938

Gnomad ASJ AF: 0.0992

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.0847

Gnomad OTH AF: 0.119

GnomAD4 exome AF: 0.0912 AC: 42265 AN: 463288 Hom.: 2111 Cov.: 4 AF XY: 0.0933 AC XY: 23012 AN XY: 246752

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.0953

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.00273

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.0897

Gnomad4 OTH exome AF: 0.100

GnomAD4 genome AF: 0.0896 AC: 13623 AN: 152092 Hom.: 629 Cov.: 32 AF XY: 0.0913 AC XY: 6786 AN XY: 74362

Gnomad4 AFR AF: 0.0951

Gnomad4 AMR AF: 0.0938

Gnomad4 ASJ AF: 0.0992

Gnomad4 EAS AF: 0.00502

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.0847

Gnomad4 OTH AF: 0.118

Alfa AF: 0.0893 Hom.: 89

Bravo AF: 0.0870

Asia WGS AF: 0.0590 AC: 205 AN: 3478

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	clinical testing	GeneDx	May 14, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.6
DANN	Benign	0.77

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: rs60476423; hg19: chr14-68194093;