14-35683971-T-G

Position:

• chr14-35683971-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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=0.08192769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGAPA1	NM_001346249.2	c.4309A>C	p.Thr1437Pro	missense_variant	21/42	ENST00000680220.1	NP_001333178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALGAPA1	ENST00000680220.1	c.4309A>C	p.Thr1437Pro	missense_variant	21/42		NM_001346249.2	ENSP00000506280.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;T;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.52	T;T;T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.082	T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.69	N;N;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.75	N;N;.;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.19	T;T;.;T;T
Sift4G	Benign	0.29	T;T;.;T;T
Polyphen		0.0	B;B;.;.;B
Vest4		0.10
MutPred		0.072		Gain of phosphorylation at T933 (P = 0.151);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

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: rs2274068; hg19: chr14-36153177;