14-35539615-A-G

Position:

• chr14-35539615-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001346247.2(RALGAPA1):​c.6323T>C​(p.Met2108Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RALGAPA1 NM_001346247.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.00

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.177823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGAPA1	NM_001346249.2	c.*99T>C		3_prime_UTR_variant	42/42	ENST00000680220.1	NP_001333178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALGAPA1	ENST00000680220	c.*99T>C		3_prime_UTR_variant	42/42		NM_001346249.2	ENSP00000506280.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461824 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2023

The c.6179T>C (p.M2060T) alteration is located in exon 40 (coding exon 40) of the RALGAPA1 gene. This alteration results from a T to C substitution at nucleotide position 6179, causing the methionine (M) at amino acid position 2060 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.0064	.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Uncertain	0.24	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.44	N;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.36
MutPred		0.21		Gain of relative solvent accessibility (P = 0.005);.;
MVP		0.36
MPC		0.95
ClinPred		0.84	D
GERP RS		5.5

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: rs1341153640; hg19: chr14-36008821;