Variant 7-39686705-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP4BS2

The NM_005402.4(RALA):c.38C>T(p.Ala13Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,461,852 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: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

RALA
NM_005402.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.15

Variant links:

Genes affected

RALA (HGNC:9839): (RAS like proto-oncogene A) The product of this gene belongs to the small GTPase superfamily, Ras family of proteins. GTP-binding proteins mediate the transmembrane signaling initiated by the occupancy of certain cell surface receptors. This gene encodes a low molecular mass ras-like GTP-binding protein that shares about 50% similarity with other ras proteins. [provided by RefSeq, Jul 2008]

RALA links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a chain Ras-related protein Ral-A (size 202) in uniprot entity RALA_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_005402.4

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RALA. . Gene score misZ 2.7026 (greater than the threshold 3.09). Trascript score misZ 3.5068 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, Hiatt-Neu-Cooper neurodevelopmental syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.3467797).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RALA	NM_005402.4 linkuse as main transcript	c.38C>T	p.Ala13Val	missense_variant	2/5	ENST00000005257.7	NP_005393.2
RALA	XM_047420681.1 linkuse as main transcript	c.38C>T	p.Ala13Val	missense_variant	2/5		XP_047276637.1
RALA	XM_047420682.1 linkuse as main transcript	c.38C>T	p.Ala13Val	missense_variant	3/6		XP_047276638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RALA	ENST00000005257.7 linkuse as main transcript	c.38C>T	p.Ala13Val	missense_variant	2/5	1	NM_005402.4	ENSP00000005257	P1
RALA	ENST00000436179.1 linkuse as main transcript	c.38C>T	p.Ala13Val	missense_variant	2/3	2		ENSP00000388975
RALA	ENST00000434466.1 linkuse as main transcript	c.20C>T	p.Ala7Val	missense_variant, NMD_transcript_variant	1/5	3		ENSP00000413227
RALA	ENST00000468201.1 linkuse as main transcript	n.262-9980C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727230

show subpopulations

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:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 13 of the RALA protein (p.Ala13Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RALA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1367953). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RALA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.096

T;.

Eigen

Benign

0.028

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.12

N;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.18

Sift

Benign

0.35

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.0010

B;.

Vest4

0.37

MutPred

0.39

Loss of disorder (P = 0.0926);Loss of disorder (P = 0.0926);

MVP

0.86

MPC

1.3

ClinPred

0.92

GERP RS

5.9

Varity_R

0.24

gMVP

0.92

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over