7-39686671-G-A

Position:

chr7-39686671-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1PP2BP4_StrongBP6_Very_StrongBS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 10.0

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 6 pathogenic changes around while only 0 benign (100%) in NM_005402.4

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.

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	Protein
RALA	NM_005402.4 linkuse as main transcript	c.4G>A	p.Ala2Thr	missense_variant	2/5	ENST00000005257.7	NP_005393.2
RALA	XM_047420681.1 linkuse as main transcript	c.4G>A	p.Ala2Thr	missense_variant	2/5		XP_047276637.1
RALA	XM_047420682.1 linkuse as main transcript	c.4G>A	p.Ala2Thr	missense_variant	3/6		XP_047276638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RALA	ENST00000005257.7 linkuse as main transcript	c.4G>A	p.Ala2Thr	missense_variant	2/5	1	NM_005402.4	ENSP00000005257	P1
RALA	ENST00000436179.1 linkuse as main transcript	c.4G>A	p.Ala2Thr	missense_variant	2/3	2		ENSP00000388975
RALA	ENST00000468201.1 linkuse as main transcript	n.262-10014G>A		intron_variant, non_coding_transcript_variant		4
RALA	ENST00000434466.1 linkuse as main transcript			upstream_gene_variant		3		ENSP00000413227

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

244

AN:

152112

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00190

AC XY:

258

AN XY:

135882

show subpopulations

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.:

Cov.:

AF XY:

0.00148

AC XY:

1078

AN XY:

726834

show subpopulations

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.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74432

show subpopulations

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.:

Bravo

AF:

0.000725

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00197

AC:

239

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.099

T;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.91

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.72

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over