Genetic Variant RALGAPA2:p.Tyr1773Tyr (chr20-20495165-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020343.4(RALGAPA2):c.5319C>T(p.Tyr1773Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,611,074 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 37 hom. )

Consequence

RALGAPA2
NM_020343.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.49

Variant links:

Genes affected

RALGAPA2 (HGNC:16207): (Ral GTPase activating protein catalytic subunit alpha 2) Predicted to enable GTPase activator activity and protein heterodimerization activity. Predicted to be involved in activation of GTPase activity. Predicted to act upstream of or within Ral protein signal transduction; regulation of exocyst localization; and regulation of protein localization. Located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

RALGAPA2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 20-20495165-G-A is Benign according to our data. Variant chr20-20495165-G-A is described in ClinVar as [Benign]. Clinvar id is 789355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.49 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00526 (7680/1458790) while in subpopulation AMR AF= 0.0217 (968/44650). AF 95% confidence interval is 0.0205. There are 37 homozygotes in gnomad4_exome. There are 3748 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RALGAPA2	NM_020343.4 link	c.5319C>T	p.Tyr1773Tyr	synonymous_variant	Exon 36 of 40	ENST00000202677.12	NP_065076.2	Q2PPJ7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RALGAPA2	ENST00000202677.12 link	c.5319C>T	p.Tyr1773Tyr	synonymous_variant	Exon 36 of 40	5	NM_020343.4	ENSP00000202677.6	Q2PPJ7-1
RALGAPA2	ENST00000430436.5 link	c.4767C>T	p.Tyr1589Tyr	synonymous_variant	Exon 30 of 33	5		ENSP00000400085.1	H7C1F9
RALGAPA2	ENST00000427175.2 link	c.549C>T	p.Tyr183Tyr	synonymous_variant	Exon 5 of 6	2		ENSP00000388695.1	H7BZA8

Frequencies

GnomAD3 genomes

AF:

0.00423

AC:

644

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00871

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00500

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00535

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00734

AC:

1828

AN:

248924

Hom.:

AF XY:

0.00622

AC XY:

840

AN XY:

135036

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.0235

Gnomad ASJ exome

AF:

0.00477

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00409

Gnomad FIN exome

AF:

0.00817

Gnomad NFE exome

AF:

0.00538

Gnomad OTH exome

AF:

0.00696

GnomAD4 exome

AF:

0.00526

AC:

7680

AN:

1458790

Hom.:

Cov.:

AF XY:

0.00516

AC XY:

3748

AN XY:

725708

show subpopulations

Gnomad4 AFR exome

AF:

0.000957

Gnomad4 AMR exome

AF:

0.0217

Gnomad4 ASJ exome

AF:

0.00457

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00427

Gnomad4 FIN exome

AF:

0.00705

Gnomad4 NFE exome

AF:

0.00504

Gnomad4 OTH exome

AF:

0.00364

GnomAD4 genome

AF:

0.00423

AC:

644

AN:

152284

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

326

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.00870

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.00500

Gnomad4 NFE

AF:

0.00535

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00480

Hom.:

Bravo

AF:

0.00478

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 11, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

7.4

DANN

Benign

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over