Genetic Variant ENST00000549913.6:n.4757C>T (chr12-112898450-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000549913.6(RPH3A):n.4757C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0398 in 152,316 control chromosomes in the GnomAD database, including 141 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 0.040 ( 141 hom., cov: 32)

Exomes 𝑓: 0.11 ( 0 hom. )

Consequence

RPH3A
ENST00000549913.6 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.85

Publications

4 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=-0.97).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPH3A	NM_001143854.2 link	c.*1670C>T		3_prime_UTR_variant	Exon 22 of 22	ENST00000389385.9	NP_001137326.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RPH3A	ENST00000549913.6 link	n.4757C>T	non_coding_transcript_exon_variant	Exon 14 of 14	1
RPH3A	ENST00000389385.9 link	c.*1670C>T	3_prime_UTR_variant	Exon 22 of 22	1	NM_001143854.2	ENSP00000374036.4	Q9Y2J0-1
RPH3A	ENST00000549324.1 link	n.2262C>T	non_coding_transcript_exon_variant	Exon 2 of 2	4
RPH3A	ENST00000415485.7 link	c.*1670C>T	3_prime_UTR_variant	Exon 21 of 21	5		ENSP00000405357.3	Q9Y2J0-1

Frequencies

GnomAD3 genomes

AF:

0.0397

AC:

6041

AN:

152160

Hom.:

140

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0414

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0253

Gnomad ASJ

AF:

0.0746

Gnomad EAS

AF:

0.00250

Gnomad SAS

AF:

0.0846

Gnomad FIN

AF:

0.0579

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0366

Gnomad OTH

AF:

0.0412

GnomAD4 exome

AF:

0.105

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0625

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.133

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0397

AC:

6052

AN:

152278

Hom.:

141

Cov.:

AF XY:

0.0423

AC XY:

3147

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0413

AC:

1716

AN:

41560

American (AMR)

AF:

0.0252

AC:

385

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0746

AC:

259

AN:

3470

East Asian (EAS)

AF:

0.00251

AC:

AN:

5188

South Asian (SAS)

AF:

0.0847

AC:

408

AN:

4818

European-Finnish (FIN)

AF:

0.0579

AC:

614

AN:

10612

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0367

AC:

2493

AN:

68012

Other (OTH)

AF:

0.0450

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

316

632

948

1264

1580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0394

Hom.:

Bravo

AF:

0.0354

Asia WGS

AF:

0.0730

AC:

254

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.067

(source)

DANN

Benign

0.46

PhyloP100

-1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over