7-39686740-G-A

Position:

• chr7-39686740-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_005402.4(RALA):​c.73G>A​(p.Val25Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V25L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RALA NM_005402.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 7-39686740-G-A is Pathogenic according to our data. Variant chr7-39686740-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-39686740-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALA	NM_005402.4	c.73G>A	p.Val25Met	missense_variant	2/5	ENST00000005257.7	NP_005393.2
RALA	XM_047420681.1	c.73G>A	p.Val25Met	missense_variant	2/5		XP_047276637.1
RALA	XM_047420682.1	c.73G>A	p.Val25Met	missense_variant	3/6		XP_047276638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALA	ENST00000005257.7	c.73G>A	p.Val25Met	missense_variant	2/5	1	NM_005402.4	ENSP00000005257	P1
RALA	ENST00000436179.1	c.73G>A	p.Val25Met	missense_variant	2/3	2		ENSP00000388975
RALA	ENST00000434466.1	c.55G>A	p.Val19Met	missense_variant, NMD_transcript_variant	1/5	3		ENSP00000413227
RALA	ENST00000468201.1	n.262-9945G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 29, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RALA function (PMID: 30500825). 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 expected to disrupt RALA protein function. ClinVar contains an entry for this variant (Variation ID: 521019). This missense change has been observed in individual(s) with RALA-related conditions (PMID: 30500825, 30761613). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 25 of the RALA protein (p.Val25Met). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2024	Published functional studies demonstrate a damaging effect with altered GTPase activity and effector protein binding (PMID: 30500825); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30500825, 30761613, 29346770, 33875846, 34615535, 33057194, 35982159) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hiatt-Neu-Cooper neurodevelopmental syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Hiatt-Neu-Cooper neurodevelopmental syndrome (MIM#619311). However, gain of function is also suspected (PMID: 30500825). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.(Val25Leu)) has been reported as pathogenic (ClinVar), and observed as de novo in monozygotic twins with profound intellectual disability, absent speech and an abnormal MRI (PMID: 30500825). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic (LOVD, ClinVar), and observed in at least three de novo individuals with intellectual disability and speech delay (PMID: 30500825). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 06, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2019

- -

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	4.8	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.77
MutPred		0.83		Loss of catalytic residue at V25 (P = 0.0241);Loss of catalytic residue at V25 (P = 0.0241);
MVP		0.96
MPC		2.6
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.99

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: rs1554297905; hg19: chr7-39726339; COSMIC: COSV50049211;