7-39686735-G-C

Variant names:

• chr7-39686735-G-C
• NM_005402.4:c.68G>C

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.68G>C​(p.Gly23Ala) 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:1
• 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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a mutagenesis_site Impaired cytokinesis, as shown by increased number of binucleate cells. No effect on interaction with EXOC2 and EXOC8. No effect on cytokinesis; when associated with R-38 or W-48. Decreased interaction with EXOC2 and EXOC8; when associated with R-38 or W-48. (size 0) in uniprot entity RALA_HUMAN
• 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, 0.901
• PP5: Variant 7-39686735-G-C is Pathogenic according to our data. Variant chr7-39686735-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2626855.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.68G>C	p.Gly23Ala	missense_variant	Exon 2 of 5	ENST00000005257.7	NP_005393.2
RALA	XM_047420681.1	c.68G>C	p.Gly23Ala	missense_variant	Exon 2 of 5		XP_047276637.1
RALA	XM_047420682.1	c.68G>C	p.Gly23Ala	missense_variant	Exon 3 of 6		XP_047276638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RALA	ENST00000005257.7	c.68G>C	p.Gly23Ala	missense_variant	Exon 2 of 5	1	NM_005402.4	ENSP00000005257.2
RALA	ENST00000436179.1	c.68G>C	p.Gly23Ala	missense_variant	Exon 2 of 3	2		ENSP00000388975.1
RALA	ENST00000434466.1	n.47G>C		non_coding_transcript_exon_variant	Exon 1 of 5	3		ENSP00000413227.1
RALA	ENST00000468201.1	n.262-9950G>C		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

Hiatt-Neu-Cooper neurodevelopmental syndrome Pathogenic:1

Feb 21, 2023

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.6	L;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.98	D;.
Vest4		0.59
MutPred		0.80		Loss of glycosylation at S22 (P = 0.035);Loss of glycosylation at S22 (P = 0.035);
MVP		0.93
MPC		2.2
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.96

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: chr7-39726334;