Genetic Variant RPH3A:c.1775+173G>A (chr12-112891176-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.65

Publications

7 publications found

Variant links:

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

RPH3A links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPH3A	NM_001143854.2 link	c.1775+173G>A		intron_variant	Intron 19 of 21	ENST00000389385.9	NP_001137326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPH3A	ENST00000389385.9 link	c.1775+173G>A		intron_variant	Intron 19 of 21	1	NM_001143854.2	ENSP00000374036.4		Q9Y2J0-1

Frequencies

GnomAD3 genomes

AF:

0.294

AC:

44643

AN:

152032

Hom.:

8021

Cov.:

show subpopulations

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.:

AF XY:

0.373

AC XY:

104939

AN XY:

281410

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

5963

11926

17890

23853

29816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2002

4004

6006

8008

10010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.293

AC:

44648

AN:

152152

Hom.:

8020

Cov.:

AF XY:

0.296

AC XY:

22000

AN XY:

74380

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1501

3001

4502

6002

7503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

456

912

1368

1824

2280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.50

PhyloP100

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over