Variant chr14-35572564-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_001346249.2(RALGAPA1):c.7364C>A(p.Pro2455Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RALGAPA1
NM_001346249.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGAPA1	NM_001346249.2 linkuse as main transcript	c.7364C>A	p.Pro2455Gln	missense_variant	38/42	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.7364C>A	p.Pro2455Gln	missense_variant	38/42		NM_001346249.2	ENSP00000506280.1		A0A7P0TAR5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.93e-7

AC:

AN:

1444020

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718004

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

9.05e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;.;D;T;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.5

M;M;.;.;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.6

D;D;D;.;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

D;D;D;.;D;D

Sift4G

Uncertain

0.0030

D;D;D;.;D;D

Polyphen

1.0

D;D;.;.;.;D

Vest4

0.60

MutPred

0.33

Loss of catalytic residue at K1948 (P = 0.0427);Loss of catalytic residue at K1948 (P = 0.0427);.;.;.;.;

MVP

0.82

MPC

1.7

ClinPred

1.0

GERP RS

5.2

Varity_R

0.75

gMVP

0.44

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over