7-39690395-A-G

Variant names:

• chr7-39690395-A-G
• NM_005402.4:c.128A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_005402.4(RALA):​c.128A>G​(p.Tyr43Cys) 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. 12/21 in silico tools predict a damaging 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:1
• 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• 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, 0.973
• PP5: Variant 7-39690395-A-G is Pathogenic according to our data. Variant chr7-39690395-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3893366.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	c.128A>G	p.Tyr43Cys	missense_variant	Exon 3 of 5	ENST00000005257.7	NP_005393.2
RALA	XM_047420681.1	c.128A>G	p.Tyr43Cys	missense_variant	Exon 3 of 5		XP_047276637.1
RALA	XM_047420682.1	c.128A>G	p.Tyr43Cys	missense_variant	Exon 4 of 6		XP_047276638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RALA	ENST00000005257.7	c.128A>G	p.Tyr43Cys	missense_variant	Exon 3 of 5	1	NM_005402.4	ENSP00000005257.2
RALA	ENST00000436179.1	c.128A>G	p.Tyr43Cys	missense_variant	Exon 3 of 3	2		ENSP00000388975.1
RALA	ENST00000434466.1	n.107A>G		non_coding_transcript_exon_variant	Exon 2 of 5	3		ENSP00000413227.1
RALA	ENST00000468201.1	n.262-6290A>G		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Aug 02, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.88	P;.
Vest4		0.73
MutPred		0.86		Loss of phosphorylation at Y43 (P = 0.0497);Loss of phosphorylation at Y43 (P = 0.0497);
MVP		0.94
MPC		2.8
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.89
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: chr7-39729994;