rs3741982

Variant names:

• chr12-112891176-G-A
• rs3741982
• NM_001143854.2:c.1775+173G>A

Variant summary

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

The NM_001143854.2(RPH3A):​c.1775+173G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 695,880 control chromosomes in the GnomAD database, including 47,093 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 0.29 (8020 hom., cov: 32)
  • Exomes 𝑓: 0.37 (39073 hom.)
• Consequence: RPH3A NM_001143854.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65
• Publications: 7 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.5 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.1775+173G>A		intron	N/A	NP_001137326.1
	RPH3A	NM_001347952.2		c.1775+173G>A		intron	N/A	NP_001334881.1
	RPH3A	NM_001347953.1		c.1775+173G>A		intron	N/A	NP_001334882.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPH3A	ENST00000389385.9	TSL:1 MANE Select	c.1775+173G>A		intron	N/A	ENSP00000374036.4
	RPH3A	ENST00000551052.5	TSL:1	c.1763+173G>A		intron	N/A	ENSP00000448297.1
	RPH3A	ENST00000549913.6	TSL:1	n.2777+173G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44643 AN: 152032 Hom.: 8021 Cov.: 32

Gnomad AFR AF: 0.0790

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.353

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.372 AC: 202457 AN: 543728 Hom.: 39073 Cov.: 7 AF XY: 0.373 AC XY: 104939 AN XY: 281410

African (AFR) AF: 0.0729 AC: 1034 AN: 14186

American (AMR) AF: 0.365 AC: 7030 AN: 19246

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 5707 AN: 14130

East Asian (EAS) AF: 0.513 AC: 15907 AN: 30984

South Asian (SAS) AF: 0.356 AC: 16814 AN: 47192

European-Finnish (FIN) AF: 0.299 AC: 8874 AN: 29722

Middle Eastern (MID) AF: 0.371 AC: 935 AN: 2522

European-Non Finnish (NFE) AF: 0.380 AC: 135512 AN: 356986

Other (OTH) AF: 0.370 AC: 10644 AN: 28760

GnomAD4 genome AF: 0.293 AC: 44648 AN: 152152 Hom.: 8020 Cov.: 32 AF XY: 0.296 AC XY: 22000 AN XY: 74380

African (AFR) AF: 0.0789 AC: 3276 AN: 41546

American (AMR) AF: 0.360 AC: 5511 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1388 AN: 3466

East Asian (EAS) AF: 0.516 AC: 2667 AN: 5164

South Asian (SAS) AF: 0.371 AC: 1786 AN: 4820

European-Finnish (FIN) AF: 0.310 AC: 3280 AN: 10582

Middle Eastern (MID) AF: 0.366 AC: 107 AN: 292

European-Non Finnish (NFE) AF: 0.375 AC: 25467 AN: 67972

Other (OTH) AF: 0.332 AC: 701 AN: 2110

Alfa AF: 0.339 Hom.: 3134

Bravo AF: 0.293

Asia WGS AF: 0.399 AC: 1388 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	15
DANN	Benign	0.50
PhyloP100		1.7
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: rs3741982; hg19: chr12-113328981; COSMIC: COSV66993597; COSMIC: COSV66993597;