12-112587857-G-A

Variant names:

• chr12-112587857-G-A
• rs11614063
• NM_001347952.2:c.-140+12538G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001347952.2(RPH3A):​c.-140+12538G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,016 control chromosomes in the GnomAD database, including 5,318 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (5318 hom., cov: 32)
• Consequence: RPH3A NM_001347952.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.488
• Publications: 8 publications found

Genes affected

RPH3A (HGNC:17056): (rabphilin 3A) The protein encoded by this gene is thought to be an effector for RAB3A, which is a small G protein that acts in the late stages of neurotransmitter exocytosis. The encoded protein may be involved in neurotransmitter release and synaptic vesicle traffic. [provided by RefSeq, Dec 2016]

RPH3A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• congenital myasthenic syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347952.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPH3A	NM_001347952.2		c.-140+12538G>A		intron	N/A	NP_001334881.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPH3A	ENST00000543106.6	TSL:2	c.-140+12538G>A		intron	N/A	ENSP00000440384.2
	RPH3A	ENST00000551593.5	TSL:4	c.-19+12538G>A		intron	N/A	ENSP00000446780.1
	RPH3A	ENST00000548197.5	TSL:4	c.-140+17313G>A		intron	N/A	ENSP00000446570.1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34250 AN: 151898 Hom.: 5299 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.0652

Gnomad EAS AF: 0.0828

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.202

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.226 AC: 34324 AN: 152016 Hom.: 5318 Cov.: 32 AF XY: 0.230 AC XY: 17121 AN XY: 74306

African (AFR) AF: 0.425 AC: 17584 AN: 41404

American (AMR) AF: 0.160 AC: 2450 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 226 AN: 3464

East Asian (EAS) AF: 0.0830 AC: 429 AN: 5170

South Asian (SAS) AF: 0.420 AC: 2018 AN: 4806

European-Finnish (FIN) AF: 0.177 AC: 1871 AN: 10574

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9153 AN: 68012

Other (OTH) AF: 0.203 AC: 428 AN: 2110

Alfa AF: 0.151 Hom.: 3569

Bravo AF: 0.226

Asia WGS AF: 0.262 AC: 912 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.2
DANN	Benign	0.71
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs11614063; hg19: chr12-113025661;