rs2274068

Positions:

• chr14-35683971-T-C
• chr14-35683971-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001346249.2(RALGAPA1):​c.4309A>G​(p.Thr1437Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,602,726 control chromosomes in the GnomAD database, including 56,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (12721 hom., cov: 32)
  • Exomes 𝑓: 0.22 (43691 hom.)
• Consequence: RALGAPA1 NM_001346249.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -19 ACMG points.

• 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=1.09732855E-5).
• BP6: Variant 14-35683971-T-C is Benign according to our data. Variant chr14-35683971-T-C is described in ClinVar as [Benign]. Clinvar id is 1327935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGAPA1	NM_001346249.2	c.4309A>G	p.Thr1437Ala	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>G	p.Thr1437Ala	missense_variant	21/42		NM_001346249.2	ENSP00000506280.1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52837 AN: 151886 Hom.: 12683 Cov.: 32

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.302

GnomAD3 exomes AF: 0.278 AC: 68472 AN: 245998 Hom.: 12392 AF XY: 0.274 AC XY: 36512 AN XY: 133126

Gnomad AFR exome AF: 0.676

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.544

Gnomad SAS exome AF: 0.391

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.216 AC: 313826 AN: 1450720 Hom.: 43691 Cov.: 32 AF XY: 0.220 AC XY: 158851 AN XY: 721632

Gnomad4 AFR exome AF: 0.682

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.204

Gnomad4 EAS exome AF: 0.603

Gnomad4 SAS exome AF: 0.385

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.173

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.348 AC: 52925 AN: 152006 Hom.: 12721 Cov.: 32 AF XY: 0.352 AC XY: 26167 AN XY: 74284

Gnomad4 AFR AF: 0.670

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.566

Gnomad4 SAS AF: 0.406

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.304

Alfa AF: 0.217 Hom.: 11013

Bravo AF: 0.360

TwinsUK AF: 0.174 AC: 644

ALSPAC AF: 0.184 AC: 709

ESP6500AA AF: 0.661 AC: 2911

ESP6500EA AF: 0.178 AC: 1527

ExAC AF: 0.289 AC: 35055

Asia WGS AF: 0.516 AC: 1793 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.8
DANN	Benign	0.31
DEOGEN2	Benign	0.019	T;.;T;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.30	T;T;T;T;T
MetaRNN	Benign	0.000011	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N;N;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.29	N;N;.;N;N
REVEL	Benign	0.29
Sift	Benign	0.71	T;T;.;T;T
Sift4G	Benign	0.80	T;T;.;T;T
Polyphen		0.0	B;B;.;.;B
Vest4		0.031
MPC		0.68
ClinPred		0.00094	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.14

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; COSMIC: COSV51896000; COSMIC: COSV51896000;