7-39686671-G-A

Position:

• chr7-39686671-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1 PP2 BP4_Strong BP6_Very_Strong BS2

The NM_005402.4(RALA):​c.4G>A​(p.Ala2Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,613,228 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: RALA NM_005402.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B: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 Benign. Variant got -13 ACMG points.

• PM1: In a chain Ras-related protein Ral-A (size 202) in uniprot entity RALA_HUMAN there are 17 pathogenic changes around while only 6 benign (74%) in NM_005402.4
• PP2: Missense variant where missense usually causes diseases, RALA
• BP4: Computational evidence support a benign effect (MetaRNN=0.011703938).
• BP6: Variant 7-39686671-G-A is Benign according to our data. Variant chr7-39686671-G-A is described in ClinVar as [Benign]. Clinvar id is 1600063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RALA	NM_005402.4	c.4G>A	p.Ala2Thr	missense_variant	2/5	ENST00000005257.7
RALA	XM_047420681.1	c.4G>A	p.Ala2Thr	missense_variant	2/5
RALA	XM_047420682.1	c.4G>A	p.Ala2Thr	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RALA	ENST00000005257.7	c.4G>A	p.Ala2Thr	missense_variant	2/5	1	NM_005402.4	P1
RALA	ENST00000436179.1	c.4G>A	p.Ala2Thr	missense_variant	2/3	2
RALA	ENST00000468201.1	n.262-10014G>A		intron_variant, non_coding_transcript_variant		4
RALA	ENST00000434466.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152112 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00194 AC: 488 AN: 251420 Hom.: 3 AF XY: 0.00190 AC XY: 258 AN XY: 135882

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00154 AC: 2252 AN: 1460998 Hom.: 5 Cov.: 30 AF XY: 0.00148 AC XY: 1078 AN XY: 726834

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.00141

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152230 Hom.: 1 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74432

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.000725

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00197 AC: 239

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	RALA: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.91	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.053	T;T
Polyphen		0.85	P;.
Vest4		0.62
MVP		0.84
MPC		2.3
ClinPred		0.29	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.81

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: rs148748965; hg19: chr7-39726270;