rs2274068

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001346249.2(RALGAPA1):c.4309A>G(p.Thr1437Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,602,726 control chromosomes in the GnomAD database, including 56,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 12721 hom., cov: 32)

Exomes 𝑓: 0.22 ( 43691 hom. )

Consequence

RALGAPA1
NM_001346249.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.214

Publications

31 publications found

Variant links:

Genes affected

RALGAPA1 (HGNC:17770): (Ral GTPase activating protein catalytic subunit alpha 1) This gene encodes a major subunit of the RAL-GTPase activating protein. A similar protein in mouse binds E12, a transcriptional regulator of immunoglobulin genes. The mouse protein also functions in skeletal muscle by binding to the regulatory 14-3-3 proteins upon stimulation with insulin or muscle contraction. A pseudogene of this gene has been identified on chromosome 9. [provided by RefSeq, Oct 2016]

RALGAPA1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RALGAPA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.09732855E-5).

BP6

Variant 14-35683971-T-C is Benign according to our data. Variant chr14-35683971-T-C is described in ClinVar as Benign. ClinVar VariationId is 1327935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RALGAPA1	NM_001346249.2 link	c.4309A>G	p.Thr1437Ala	missense_variant	Exon 21 of 42	ENST00000680220.1	NP_001333178.1	Q6GYQ0A0A7P0TAR5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RALGAPA1	ENST00000680220.1 link	c.4309A>G	p.Thr1437Ala	missense_variant	Exon 21 of 42		NM_001346249.2	ENSP00000506280.1		A0A7P0TAR5

Frequencies

GnomAD3 genomes

AF:

0.348

AC:

52837

AN:

151886

Hom.:

12683

Cov.:

show subpopulations

Gnomad AFR

AF:

0.670

Gnomad AMI

AF:

0.212

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.209

Gnomad EAS

AF:

0.567

Gnomad SAS

AF:

0.409

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.182

Gnomad OTH

AF:

0.302

GnomAD2 exomes

AF:

0.278

AC:

68472

AN:

245998

AF XY:

0.274

show subpopulations

Gnomad AFR exome

AF:

0.676

Gnomad AMR exome

AF:

0.229

Gnomad ASJ exome

AF:

0.199

Gnomad EAS exome

AF:

0.544

Gnomad FIN exome

AF:

0.229

Gnomad NFE exome

AF:

0.181

Gnomad OTH exome

AF:

0.234

GnomAD4 exome

AF:

0.216

AC:

313826

AN:

1450720

Hom.:

43691

Cov.:

AF XY:

0.220

AC XY:

158851

AN XY:

721632

show subpopulations

African (AFR)

AF:

0.682

AC:

22458

AN:

32914

American (AMR)

AF:

0.223

AC:

9616

AN:

43088

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

5253

AN:

25772

East Asian (EAS)

AF:

0.603

AC:

23833

AN:

39526

South Asian (SAS)

AF:

0.385

AC:

32620

AN:

84830

European-Finnish (FIN)

AF:

0.229

AC:

12201

AN:

53266

Middle Eastern (MID)

AF:

0.256

AC:

1461

AN:

5718

European-Non Finnish (NFE)

AF:

0.173

AC:

191554

AN:

1105610

Other (OTH)

AF:

0.247

AC:

14830

AN:

59996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

9944

19889

29833

39778

49722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7282

14564

21846

29128

36410

<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:

0.348

AC:

52925

AN:

152006

Hom.:

12721

Cov.:

AF XY:

0.352

AC XY:

26167

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.670

AC:

27780

AN:

41450

American (AMR)

AF:

0.256

AC:

3907

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.209

AC:

726

AN:

3468

East Asian (EAS)

AF:

0.566

AC:

2916

AN:

5154

South Asian (SAS)

AF:

0.406

AC:

1951

AN:

4808

European-Finnish (FIN)

AF:

0.223

AC:

2360

AN:

10560

Middle Eastern (MID)

AF:

0.272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.182

AC:

12370

AN:

67980

Other (OTH)

AF:

0.304

AC:

643

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1447

2894

4341

5788

7235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

484

968

1452

1936

2420

<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:

0.241

Hom.:

19927

Bravo

AF:

0.360

TwinsUK

AF:

0.174

AC:

644

ALSPAC

AF:

0.184

AC:

709

ESP6500AA

AF:

0.661

AC:

2911

ESP6500EA

AF:

0.178

AC:

1527

ExAC

AF:

0.289

AC:

35055

Asia WGS

AF:

0.516

AC:

1793

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

9.8

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.019

T;.;T;.;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.30

T;T;T;T;T

MetaRNN

Benign

0.000011

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.69

N;N;.;.;.

PhyloP100

0.21

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.29

N;N;.;N;N

REVEL

Benign

0.29

Sift

Benign

0.71

T;T;.;T;T

Sift4G

Benign

0.80

T;T;.;T;T

Polyphen

0.0

B;B;.;.;B

Vest4

0.031

MPC

0.68

ClinPred

0.00094

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.14

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over