Variant 7-39690428-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_005402.4(RALA):c.161A>G(p.Lys54Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RALA
NM_005402.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

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:

RALA (HGNC:):

RALA links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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

PM2

Very rare variant in population databases, with high coverage;

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALA	NM_005402.4 linkuse as main transcript	c.161A>G	p.Lys54Arg	missense_variant	3/5	ENST00000005257.7	NP_005393.2	P11233
RALA	XM_047420681.1 linkuse as main transcript	c.161A>G	p.Lys54Arg	missense_variant	3/5		XP_047276637.1
RALA	XM_047420682.1 linkuse as main transcript	c.161A>G	p.Lys54Arg	missense_variant	4/6		XP_047276638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RALA	ENST00000005257.7 linkuse as main transcript	c.161A>G	p.Lys54Arg	missense_variant	3/5	1	NM_005402.4	ENSP00000005257.2	P11233
RALA	ENST00000436179.1 linkuse as main transcript	c.161A>G	p.Lys54Arg	missense_variant	3/3	2		ENSP00000388975.1	C9JPE8
RALA	ENST00000434466.1 linkuse as main transcript	n.140A>G		non_coding_transcript_exon_variant	2/5	3		ENSP00000413227.1	H7C3P7
RALA	ENST00000468201.1 linkuse as main transcript	n.262-6257A>G		intron_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

GeneDx

Jul 01, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

-0.018

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

T;D

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.40

N;.

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.47

Sift

Benign

0.049

D;T

Sift4G

Uncertain

0.030

D;T

Polyphen

0.0010

B;.

Vest4

0.59

MutPred

0.49

Loss of ubiquitination at K54 (P = 0.0155);Loss of ubiquitination at K54 (P = 0.0155);

MVP

0.96

MPC

1.1

ClinPred

0.76

GERP RS

4.9

Varity_R

0.36

gMVP

0.83

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