chr7-39686776-G-A

Variant names:

• chr7-39686776-G-A
• rs765338145
• NM_005402.4:c.109G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_005402.4(RALA):​c.109G>A​(p.Asp37Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RALA NM_005402.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Uncertain_significance. Variant got 4 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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2721069).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RALA	NM_005402.4	c.109G>A	p.Asp37Asn	missense_variant	Exon 2 of 5	ENST00000005257.7	NP_005393.2
RALA	XM_047420681.1	c.109G>A	p.Asp37Asn	missense_variant	Exon 2 of 5		XP_047276637.1
RALA	XM_047420682.1	c.109G>A	p.Asp37Asn	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.109G>A	p.Asp37Asn	missense_variant	Exon 2 of 5	1	NM_005402.4	ENSP00000005257.2
RALA	ENST00000436179.1	c.109G>A	p.Asp37Asn	missense_variant	Exon 2 of 3	2		ENSP00000388975.1
RALA	ENST00000434466.1	n.88G>A		non_coding_transcript_exon_variant	Exon 1 of 5	3		ENSP00000413227.1
RALA	ENST00000468201.1	n.262-9909G>A		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250698 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135488

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456160 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724826

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt RALA protein function. This variant has not been reported in the literature in individuals affected with RALA-related conditions. This variant is present in population databases (rs765338145, gnomAD 0.006%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 37 of the RALA protein (p.Asp37Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	29
DANN	Benign	0.93
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.38	N;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.0	N;D
REVEL	Uncertain	0.39
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.82	P;.
Vest4		0.66
MutPred		0.38		Loss of phosphorylation at Y36 (P = 0.1509);Loss of phosphorylation at Y36 (P = 0.1509);
MVP		0.80
MPC		1.3
ClinPred		0.28	T
GERP RS		5.9
Varity_R		0.60
gMVP		0.97

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: rs765338145; hg19: chr7-39726375;