NM_001346249.2:c.5329-1569T>G

Variant names:

• chr14-35660765-A-C
• rs4982303
• NM_001346249.2:c.5329-1569T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001346249.2(RALGAPA1):​c.5329-1569T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 152,030 control chromosomes in the GnomAD database, including 7,382 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (7382 hom., cov: 32)
• Consequence: RALGAPA1 NM_001346249.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 4 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, Labcorp Genetics (formerly Invitae), G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RALGAPA1	NM_001346249.2	MANE Select	c.5329-1569T>G		intron	N/A	NP_001333178.1
	RALGAPA1	NM_001330075.3		c.5188-1569T>G		intron	N/A	NP_001317004.1
	RALGAPA1	NM_001346248.2		c.5188-1569T>G		intron	N/A	NP_001333177.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RALGAPA1	ENST00000680220.1	MANE Select	c.5329-1569T>G		intron	N/A	ENSP00000506280.1
	RALGAPA1	ENST00000307138.10	TSL:1	c.3811-1569T>G		intron	N/A	ENSP00000302647.6
	RALGAPA1	ENST00000382366.7	TSL:1	c.3850-1569T>G		intron	N/A	ENSP00000371803.3

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39343 AN: 151910 Hom.: 7341 Cov.: 32

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.231

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

GnomAD4 genome AF: 0.259 AC: 39438 AN: 152030 Hom.: 7382 Cov.: 32 AF XY: 0.261 AC XY: 19400 AN XY: 74338

African (AFR) AF: 0.526 AC: 21820 AN: 41458

American (AMR) AF: 0.195 AC: 2979 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 619 AN: 3468

East Asian (EAS) AF: 0.193 AC: 996 AN: 5174

South Asian (SAS) AF: 0.299 AC: 1441 AN: 4822

European-Finnish (FIN) AF: 0.159 AC: 1687 AN: 10604

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9237 AN: 67918

Other (OTH) AF: 0.231 AC: 489 AN: 2116

Alfa AF: 0.220 Hom.: 838

Bravo AF: 0.267

Asia WGS AF: 0.275 AC: 956 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.35
DANN	Benign	0.65
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs4982303; hg19: chr14-36129971;