7-39686713-A-G

Position:

• chr7-39686713-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32

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 (HGNC:):

ACMG classification

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 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, 0.91
• 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/exons	MANE	Protein	UniProt
RALA	NM_005402.4	c.46A>G	p.Lys16Glu	missense_variant	2/5	ENST00000005257.7	NP_005393.2
RALA	XM_047420681.1	c.46A>G	p.Lys16Glu	missense_variant	2/5		XP_047276637.1
RALA	XM_047420682.1	c.46A>G	p.Lys16Glu	missense_variant	3/6		XP_047276638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALA	ENST00000005257.7	c.46A>G	p.Lys16Glu	missense_variant	2/5	1	NM_005402.4	ENSP00000005257.2
RALA	ENST00000436179.1	c.46A>G	p.Lys16Glu	missense_variant	2/3	2		ENSP00000388975.1
RALA	ENST00000434466.1	n.25A>G		non_coding_transcript_exon_variant	1/5	3		ENSP00000413227.1
RALA	ENST00000468201.1	n.262-9972A>G		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hiatt-Neu-Cooper neurodevelopmental syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Feb 01, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 24, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Pathogenic	0.85	D
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	D
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.

Other links and lift over

hg19: chr7-39726312;