14-35570703-A-T

Position:

chr14-35570703-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001346249.2(RALGAPA1):c.7410T>A(p.Asn2470Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000298 in 1,611,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

RALGAPA1
NM_001346249.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.42

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 links:

RALGAPA1 (HGNC:):

RALGAPA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RALGAPA1. . Gene score misZ 3.5271 (greater than the threshold 3.09). Trascript score misZ 5.347 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation, complex neurodevelopmental disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.21071798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGAPA1	NM_001346249.2 linkuse as main transcript	c.7410T>A	p.Asn2470Lys	missense_variant	39/42	ENST00000680220.1	NP_001333178.1	Q6GYQ0A0A7P0TAR5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALGAPA1	ENST00000680220.1 linkuse as main transcript	c.7410T>A	p.Asn2470Lys	missense_variant	39/42		NM_001346249.2	ENSP00000506280.1		A0A7P0TAR5

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

248444

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134284

show subpopulations

Gnomad AFR exome

AF:

0.000435

Gnomad AMR exome

AF:

0.0000591

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1459238

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725844

show subpopulations

Gnomad4 AFR exome

AF:

0.000540

Gnomad4 AMR exome

AF:

0.0000451

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.000145

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000507

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2023

The c.5892T>A (p.N1964K) alteration is located in exon 38 (coding exon 38) of the RALGAPA1 gene. This alteration results from a T to A substitution at nucleotide position 5892, causing the asparagine (N) at amino acid position 1964 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 12, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.;D;T;.;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

M_CAP

Benign

0.066

MetaRNN

Benign

0.21

T;T;T;T;T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

0.81

L;L;.;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.3

N;N;D;.;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.051

T;T;D;.;D;D

Sift4G

Benign

0.17

T;T;T;.;T;T

Polyphen

0.41

B;P;.;.;.;P

Vest4

0.56

MutPred

0.47

Gain of methylation at N1964 (P = 0.0124);Gain of methylation at N1964 (P = 0.0124);.;.;.;.;

MVP

0.51

MPC

1.3

ClinPred

0.18

GERP RS

6.0

Varity_R

0.41

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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