rs2240191

Variant names:

• chr12-112897926-G-T
• rs2240191
• NM_001143854.2:c.*1146G>T

Variant summary

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

The NM_001143854.2(RPH3A):​c.*1146G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 152,200 control chromosomes in the GnomAD database, including 6,230 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 0.26 (6230 hom., cov: 32)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: RPH3A NM_001143854.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.24
• Publications: 20 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):

• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, PanelApp Australia
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143854.2. 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
	RPH3A	NM_001143854.2	MANE Select	c.*1146G>T		3_prime_UTR	Exon 22 of 22	NP_001137326.1	Q9Y2J0-1
	RPH3A	NM_001347952.2		c.*1146G>T		3_prime_UTR	Exon 22 of 22	NP_001334881.1	Q9Y2J0-1
	RPH3A	NM_001347953.1		c.*1146G>T		3_prime_UTR	Exon 22 of 22	NP_001334882.1	Q9Y2J0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPH3A	ENST00000389385.9	TSL:1 MANE Select	c.*1146G>T		3_prime_UTR	Exon 22 of 22	ENSP00000374036.4	Q9Y2J0-1
	RPH3A	ENST00000549913.6	TSL:1	n.4233G>T		non_coding_transcript_exon	Exon 14 of 14
	RPH3A	ENST00000415485.7	TSL:5	c.*1146G>T		3_prime_UTR	Exon 21 of 21	ENSP00000405357.3	Q9Y2J0-1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 40008 AN: 151956 Hom.: 6216 Cov.: 32

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.272

GnomAD4 exome AF: 0.175 AC: 22 AN: 126 Hom.: 0 Cov.: 0 AF XY: 0.149 AC XY: 14 AN XY: 94

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.170 AC: 18 AN: 106

Other (OTH) AF: 0.125 AC: 1 AN: 8

GnomAD4 genome AF: 0.263 AC: 40071 AN: 152074 Hom.: 6230 Cov.: 32 AF XY: 0.262 AC XY: 19450 AN XY: 74338

African (AFR) AF: 0.411 AC: 17056 AN: 41456

American (AMR) AF: 0.317 AC: 4838 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 751 AN: 3470

East Asian (EAS) AF: 0.445 AC: 2296 AN: 5158

South Asian (SAS) AF: 0.196 AC: 945 AN: 4824

European-Finnish (FIN) AF: 0.152 AC: 1612 AN: 10592

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11841 AN: 67978

Other (OTH) AF: 0.272 AC: 575 AN: 2114

Alfa AF: 0.209 Hom.: 6185

Bravo AF: 0.288

Asia WGS AF: 0.306 AC: 1063 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.15
DANN	Benign	0.78
PhyloP100		-2.2
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: rs2240191; hg19: chr12-113335731;