NM_001346249.2:c.7514G>C

Variant names:

• chr14-35549217-C-G
• rs796052176
• NM_001346249.2:c.7514G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 207899.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346249.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RALGAPA1	NM_001346249.2	MANE Select	c.7514G>C	p.Arg2505Pro	missense	Exon 40 of 42	NP_001333178.1	A0A7P0TAR5
	RALGAPA1	NM_001330075.3		c.7373G>C	p.Arg2458Pro	missense	Exon 39 of 41	NP_001317004.1	A0A1B0GUI1
	RALGAPA1	NM_001346248.2		c.7373G>C	p.Arg2458Pro	missense	Exon 39 of 42	NP_001333177.1	A0A1B0GUI1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RALGAPA1	ENST00000680220.1	MANE Select	c.7514G>C	p.Arg2505Pro	missense	Exon 40 of 42	ENSP00000506280.1	A0A7P0TAR5
	RALGAPA1	ENST00000307138.10	TSL:1	c.5996G>C	p.Arg1999Pro	missense	Exon 39 of 40	ENSP00000302647.6	Q6GYQ0-2
	RALGAPA1	ENST00000382366.7	TSL:1	c.6035G>C	p.Arg2012Pro	missense	Exon 40 of 42	ENSP00000371803.3	Q6GYQ0-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.80
Sift	Benign	0.056	T
Sift4G	Uncertain	0.038	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.60		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
Mutation Taster		=33/67	disease causing

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

Other links and lift over

dbSNP: rs796052176; hg19: chr14-36018423;