Variant 7-39686713-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_ModeratePP5_Moderate

The NM_005402.4(RALA):c.46A>G(p.Lys16Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RALA
NM_005402.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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 the RALA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 2.7026 (below the threshold of 3.09). Trascript score misZ: 3.5068 (above the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder, Hiatt-Neu-Cooper neurodevelopmental syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

PP5

Variant 7-39686713-A-G is Pathogenic according to our data. Variant chr7-39686713-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2582518.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RALA	NM_005402.4 link	c.46A>G	p.Lys16Glu	missense_variant	Exon 2 of 5	ENST00000005257.7	NP_005393.2	P11233
RALA	XM_047420681.1 link	c.46A>G	p.Lys16Glu	missense_variant	Exon 2 of 5		XP_047276637.1
RALA	XM_047420682.1 link	c.46A>G	p.Lys16Glu	missense_variant	Exon 3 of 6		XP_047276638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RALA	ENST00000005257.7 link	c.46A>G	p.Lys16Glu	missense_variant	Exon 2 of 5	1	NM_005402.4	ENSP00000005257.2	P11233
RALA	ENST00000436179.1 link	c.46A>G	p.Lys16Glu	missense_variant	Exon 2 of 3	2		ENSP00000388975.1	C9JPE8
RALA	ENST00000434466.1 link	n.25A>G		non_coding_transcript_exon_variant	Exon 1 of 5	3		ENSP00000413227.1	H7C3P7
RALA	ENST00000468201.1 link	n.262-9972A>G		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hiatt-Neu-Cooper neurodevelopmental syndrome

Pathogenic:2

Feb 01, 2024

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 24, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.8

H;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.90

MutPred

0.71

Loss of methylation at K16 (P = 0.001);Loss of methylation at K16 (P = 0.001);

MVP

0.99

MPC

2.8

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.96

gMVP

1.0

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