chr12-112865531-G-T

Variant names:

• chr12-112865531-G-T
• rs1387785097
• NM_001143854.2:c.348G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001143854.2(RPH3A):​c.348G>T​(p.Glu116Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,510 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RPH3A NM_001143854.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.348G>T	p.Glu116Asp	missense	Exon 6 of 22	NP_001137326.1	Q9Y2J0-1
	RPH3A	NM_001347952.2		c.348G>T	p.Glu116Asp	missense	Exon 6 of 22	NP_001334881.1	Q9Y2J0-1
	RPH3A	NM_001347953.1		c.348G>T	p.Glu116Asp	missense	Exon 6 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.348G>T	p.Glu116Asp	missense	Exon 6 of 22	ENSP00000374036.4	Q9Y2J0-1
	RPH3A	ENST00000551052.5	TSL:1	c.336G>T	p.Glu112Asp	missense	Exon 5 of 21	ENSP00000448297.1	Q9Y2J0-2
	RPH3A	ENST00000415485.7	TSL:5	c.348G>T	p.Glu116Asp	missense	Exon 5 of 21	ENSP00000405357.3	Q9Y2J0-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251038 AF XY: 0.00000737

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461402 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727006

African (AFR) AF: 0.000120 AC: 4 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5544

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111900

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74290

African (AFR) AF: 0.0000724 AC: 3 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	0.0097	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.52
Sift	Benign	0.20	T
Sift4G	Benign	0.45	T
Polyphen		0.98	D
Vest4		0.62
MutPred		0.52		Gain of catalytic residue at K119 (P = 0)
MVP		0.82
MPC		0.88
ClinPred		0.71	D
GERP RS		2.6
Varity_R		0.091
gMVP		0.54
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 4

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

Other links and lift over

dbSNP: rs1387785097; hg19: chr12-113303336; COSMIC: COSV108231572; COSMIC: COSV108231572;