chr14-35549217-C-G

Position:

• chr14-35549217-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PP2 PP3_Moderate BP6

The NM_001346249.2(RALGAPA1):​c.7514G>C​(p.Arg2505Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RALGAPA1 NM_001346249.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 5.46

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 4 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, 0.854
• BP6: Variant 14-35549217-C-G is Benign according to our data. Variant chr14-35549217-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 207899.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGAPA1	NM_001346249.2	c.7514G>C	p.Arg2505Pro	missense_variant	40/42	ENST00000680220.1	NP_001333178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALGAPA1	ENST00000680220.1	c.7514G>C	p.Arg2505Pro	missense_variant	40/42		NM_001346249.2	ENSP00000506280

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Long QT syndrome Benign:1

Likely benign, no assertion criteria provided

research

Medical Research Institute, Tokyo Medical and Dental University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.;T;T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.2	D;D;D;.;D;D
REVEL	Pathogenic	0.80
Sift	Benign	0.056	T;T;D;.;T;T
Sift4G	Uncertain	0.038	D;D;T;.;D;D
Polyphen		1.0	D;D;.;.;.;D
Vest4		0.88
MutPred		0.60		Loss of catalytic residue at R1999 (P = 0.0407);Loss of catalytic residue at R1999 (P = 0.0407);.;.;.;.;
MVP		0.85
MPC		2.1
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.82
gMVP		0.85

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: rs796052176; hg19: chr14-36018423;