NM_001346249.2:c.1145G>T

Variant names:

• chr14-35748691-C-A
• rs1555427204
• NM_001346249.2:c.1145G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001346249.2(RALGAPA1):​c.1145G>T​(p.Ser382Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: RALGAPA1 NM_001346249.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.91
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1145G>T	p.Ser382Ile	missense	Exon 10 of 42	NP_001333178.1	A0A7P0TAR5
	RALGAPA1	NM_001330075.3		c.1145G>T	p.Ser382Ile	missense	Exon 10 of 41	NP_001317004.1	A0A1B0GUI1
	RALGAPA1	NM_001346248.2		c.1145G>T	p.Ser382Ile	missense	Exon 10 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.1145G>T	p.Ser382Ile	missense	Exon 10 of 42	ENSP00000506280.1	A0A7P0TAR5
	RALGAPA1	ENST00000307138.10	TSL:1	c.1145G>T	p.Ser382Ile	missense	Exon 10 of 40	ENSP00000302647.6	Q6GYQ0-2
	RALGAPA1	ENST00000382366.7	TSL:1	c.1145G>T	p.Ser382Ile	missense	Exon 10 of 42	ENSP00000371803.3	Q6GYQ0-7

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.24		Loss of phosphorylation at S382 (P = 0.0131)
MVP		0.60
MPC		1.9
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.79
gMVP		0.78
Mutation Taster		=78/22	polymorphism

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: rs1555427204; hg19: chr14-36217897;