7-39686740-G-T

Position:

• chr7-39686740-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_005402.4(RALA):​c.73G>T​(p.Val25Leu) 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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V25M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RALA NM_005402.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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 15 ACMG points.

• PS1: Transcript NM_005402.4 (RALA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a binding_site (size 5) in uniprot entity RALA_HUMAN there are 4 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 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.
• PP2: Missense variant where missense usually causes diseases, RALA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 7-39686740-G-T is Pathogenic according to our data. Variant chr7-39686740-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1068752.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RALA	NM_005402.4	c.73G>T	p.Val25Leu	missense_variant	2/5	ENST00000005257.7
RALA	XM_047420681.1	c.73G>T	p.Val25Leu	missense_variant	2/5
RALA	XM_047420682.1	c.73G>T	p.Val25Leu	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RALA	ENST00000005257.7	c.73G>T	p.Val25Leu	missense_variant	2/5	1	NM_005402.4	P1
RALA	ENST00000436179.1	c.73G>T	p.Val25Leu	missense_variant	2/3	2
RALA	ENST00000434466.1	c.55G>T	p.Val19Leu	missense_variant, NMD_transcript_variant	1/5	3
RALA	ENST00000468201.1	n.262-9945G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hiatt-Neu-Cooper neurodevelopmental syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 30500825). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with RALA related disorder (ClinVar ID: VCV001068752 / PMID: 30500825). The variant has been previously reported as de novo in a similarly affected individual (PMID: 30500825, 30500825). A different missense change at the same codon (p.Val25Met) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000521019). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 06, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.5	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.83		Loss of ubiquitination at K27 (P = 0.0747);Loss of ubiquitination at K27 (P = 0.0747);
MVP		0.97
MPC		2.6
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.87
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-39726339;