14-35570675-C-T

Position:

• chr14-35570675-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001346249.2(RALGAPA1):​c.7438G>A​(p.Ala2480Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RALGAPA1 NM_001346249.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.19

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGAPA1	NM_001346249.2	c.7438G>A	p.Ala2480Thr	missense_variant	39/42	ENST00000680220.1	NP_001333178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALGAPA1	ENST00000680220.1	c.7438G>A	p.Ala2480Thr	missense_variant	39/42		NM_001346249.2	ENSP00000506280.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459070 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 725792

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: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2022

The c.5920G>A (p.A1974T) alteration is located in exon 38 (coding exon 38) of the RALGAPA1 gene. This alteration results from a G to A substitution at nucleotide position 5920, causing the alanine (A) at amino acid position 1974 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;D;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	2.0	M;M;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D;D;D;.;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.17	T;T;T;.;T;T
Sift4G	Benign	0.10	T;T;D;.;T;T
Polyphen		0.039	B;B;.;.;.;B
Vest4		0.60
MutPred		0.76		Loss of methylation at R1973 (P = 0.1151);Loss of methylation at R1973 (P = 0.1151);.;.;.;.;
MVP		0.58
MPC		1.7
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.24
gMVP		0.49

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

Other links and lift over

dbSNP: rs763875051; hg19: chr14-36039881;