14-35627109-T-A

Position:

• chr14-35627109-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001346249.2(RALGAPA1):​c.6838A>T​(p.Met2280Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RALGAPA1 NM_001346249.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.38

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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=0.36314887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGAPA1	NM_001346249.2	c.6838A>T	p.Met2280Leu	missense_variant	34/42	ENST00000680220.1	NP_001333178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALGAPA1	ENST00000680220.1	c.6838A>T	p.Met2280Leu	missense_variant	34/42		NM_001346249.2	ENSP00000506280.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

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

Jan 31, 2024

The c.5320A>T (p.M1774L) alteration is located in exon 33 (coding exon 33) of the RALGAPA1 gene. This alteration results from a A to T substitution at nucleotide position 5320, causing the methionine (M) at amino acid position 1774 to be replaced by a leucine (L). 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Benign	0.028	T;.;T;T;.;.
Eigen	Benign	-0.067
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Uncertain	0.081	D
MutationAssessor	Benign	-0.36	N;N;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	N;N;N;.;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.39	T;T;T;.;T;T
Sift4G	Benign	0.68	T;T;T;.;T;T
Polyphen		0.0010	B;B;.;.;.;B
Vest4		0.36
MutPred		0.61		Loss of methylation at K1779 (P = 0.0802);Loss of methylation at K1779 (P = 0.0802);.;.;.;.;
MVP		0.67
MPC		0.65
ClinPred		0.81	D
GERP RS		5.4
Varity_R		0.43
gMVP		0.64

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.

Other links and lift over

hg19: chr14-36096315;