chr14-67727476-G-T

Variant names:

• chr14-67727476-G-T
• rs8009179
• NM_152443.3:c.658+286G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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]

ZFYVE26 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 15

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152443.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH12	NM_152443.3	MANE Select	c.658+286G>T		intron	N/A	NP_689656.2	A0A0S2Z613

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH12	ENST00000551171.6	TSL:1 MANE Select	c.658+286G>T		intron	N/A	ENSP00000449079.1	Q96NR8
	RDH12	ENST00000267502.3	TSL:5	c.658+286G>T		intron	N/A	ENSP00000267502.3	Q96NR8
	ZFYVE26	ENST00000394455.6	TSL:2	n.4032C>A		non_coding_transcript_exon	Exon 15 of 15

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

African (AFR) AF: 0.279 AC: 1092 AN: 3910

American (AMR) AF: 0.433 AC: 2378 AN: 5492

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1790 AN: 3844

East Asian (EAS) AF: 0.439 AC: 2547 AN: 5802

South Asian (SAS) AF: 0.385 AC: 10718 AN: 27836

European-Finnish (FIN) AF: 0.474 AC: 3709 AN: 7818

Middle Eastern (MID) AF: 0.398 AC: 206 AN: 518

European-Non Finnish (NFE) AF: 0.523 AC: 46631 AN: 89092

Other (OTH) AF: 0.463 AC: 3616 AN: 7806

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

African (AFR) AF: 0.342 AC: 13678 AN: 39952

American (AMR) AF: 0.550 AC: 8082 AN: 14682

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2048 AN: 3434

East Asian (EAS) AF: 0.551 AC: 2734 AN: 4964

South Asian (SAS) AF: 0.437 AC: 2038 AN: 4666

European-Finnish (FIN) AF: 0.568 AC: 5201 AN: 9164

Middle Eastern (MID) AF: 0.431 AC: 118 AN: 274

European-Non Finnish (NFE) AF: 0.651 AC: 43437 AN: 66716

Other (OTH) AF: 0.508 AC: 1031 AN: 2028

Alfa AF: 0.153 Hom.: 442

Bravo AF: 0.529

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.29
DANN	Benign	0.55
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs8009179; hg19: chr14-68194193;