14-35683969-GGT-CGC

Variant names:

• chr14-35683969-GGT-CGC
• NM_001346249.2:c.4309_4311delACCinsGCG
• RALGAPA1 p.Thr1437Ala

Variant summary

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

The NM_001346249.2(RALGAPA1):​c.4309_4311delACCinsGCG​(p.Thr1437Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RALGAPA1 NM_001346249.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.97
• 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 0 ACMG points.

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.4309_4311delACCinsGCG	p.Thr1437Ala	missense	N/A	NP_001333178.1	A0A7P0TAR5
	RALGAPA1	NM_001330075.3		c.4168_4170delACCinsGCG	p.Thr1390Ala	missense	N/A	NP_001317004.1	A0A1B0GUI1
	RALGAPA1	NM_001346248.2		c.4168_4170delACCinsGCG	p.Thr1390Ala	missense	N/A	NP_001333177.1	A0A1B0GUI1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RALGAPA1	ENST00000680220.1	MANE Select	c.4309_4311delACCinsGCG	p.Thr1437Ala	missense	N/A	ENSP00000506280.1	A0A7P0TAR5
	RALGAPA1	ENST00000307138.10	TSL:1	c.2791_2793delACCinsGCG	p.Thr931Ala	missense	N/A	ENSP00000302647.6	Q6GYQ0-2
	RALGAPA1	ENST00000382366.7	TSL:1	c.2830_2832delACCinsGCG	p.Thr944Ala	missense	N/A	ENSP00000371803.3	Q6GYQ0-7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-36153175;