chr14-35683971-T-G

Variant names:

• chr14-35683971-T-G
• rs2274068
• NM_001346249.2:c.4309A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001346249.2(RALGAPA1):​c.4309A>C​(p.Thr1437Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1437A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RALGAPA1 NM_001346249.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.214
• Publications: 31 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08192769).

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.4309A>C	p.Thr1437Pro	missense	Exon 21 of 42	NP_001333178.1	A0A7P0TAR5
	RALGAPA1	NM_001330075.3		c.4168A>C	p.Thr1390Pro	missense	Exon 20 of 41	NP_001317004.1	A0A1B0GUI1
	RALGAPA1	NM_001346248.2		c.4168A>C	p.Thr1390Pro	missense	Exon 20 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.4309A>C	p.Thr1437Pro	missense	Exon 21 of 42	ENSP00000506280.1	A0A7P0TAR5
	RALGAPA1	ENST00000307138.10	TSL:1	c.2791A>C	p.Thr931Pro	missense	Exon 20 of 40	ENSP00000302647.6	Q6GYQ0-2
	RALGAPA1	ENST00000382366.7	TSL:1	c.2830A>C	p.Thr944Pro	missense	Exon 21 of 42	ENSP00000371803.3	Q6GYQ0-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.21
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.37
Sift	Benign	0.19	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.072		Gain of phosphorylation at T933 (P = 0.151)
MVP		0.45
MPC		0.90
ClinPred		0.060	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.11
Mutation Taster		=94/6	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: rs2274068; hg19: chr14-36153177;