9-136837375-G-A

Position:

• chr9-136837375-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_024718.5(RABL6):​c.839G>A​(p.Arg280His) variant causes a missense change. The variant allele was found at a frequency of 0.00405 in 1,602,836 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (22 hom.)
• Consequence: RABL6 NM_024718.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.15

Genes affected

RABL6 (HGNC:24703): (RAB, member RAS oncogene family like 6) This gene encodes a member of the Ras superfamily of small GTPases. The encoded protein binds to both GTP and GDP and may play a role in cell growth and survival. Overexpression of this gene may play a role in breast cancer tumorigenesis, and pseudogenes of this gene are located on the long arm of chromosome 2 and the short arm of chromosome 18. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

RABL6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007768929).
• BP6: Variant 9-136837375-G-A is Benign according to our data. Variant chr9-136837375-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 769760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RABL6	NM_024718.5	c.839G>A	p.Arg280His	missense_variant	9/15	ENST00000311502.12	NP_078994.3
RABL6	NM_001173988.2	c.842G>A	p.Arg281His	missense_variant	9/15		NP_001167459.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RABL6	ENST00000311502.12	c.839G>A	p.Arg280His	missense_variant	9/15	1	NM_024718.5	ENSP00000311134.7
RABL6	ENST00000357466.6	c.839G>A	p.Arg280His	missense_variant	9/10	1		ENSP00000350056.2

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 476 AN: 152174 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00473

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00305 AC: 682 AN: 223256 Hom.: 4 AF XY: 0.00319 AC XY: 392 AN XY: 122746

Gnomad AFR exome AF: 0.000925

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00147

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00194

Gnomad FIN exome AF: 0.00536

Gnomad NFE exome AF: 0.00457

Gnomad OTH exome AF: 0.00235

GnomAD4 exome AF: 0.00415 AC: 6017 AN: 1450544 Hom.: 22 Cov.: 31 AF XY: 0.00409 AC XY: 2946 AN XY: 720730

Gnomad4 AFR exome AF: 0.000451

Gnomad4 AMR exome AF: 0.00115

Gnomad4 ASJ exome AF: 0.00158

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00196

Gnomad4 FIN exome AF: 0.00478

Gnomad4 NFE exome AF: 0.00483

Gnomad4 OTH exome AF: 0.00244

GnomAD4 genome AF: 0.00313 AC: 476 AN: 152292 Hom.: 1 Cov.: 33 AF XY: 0.00312 AC XY: 232 AN XY: 74470

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00725

Gnomad4 NFE AF: 0.00473

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00389 Hom.: 0

Bravo AF: 0.00247

ESP6500AA AF: 0.00207 AC: 8

ESP6500EA AF: 0.00392 AC: 32

ExAC AF: 0.00294 AC: 352

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	RABL6: BP4 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.97	D;D;D;D
MetaRNN	Benign	0.0078	T;T;T;T
MetaSVM	Uncertain	-0.0023	T
MutationAssessor	Uncertain	2.6	M;.;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.5	D;D;D;.
REVEL	Benign	0.24
Sift	Uncertain	0.0080	D;D;D;.
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.35
MVP		0.61
MPC		0.034
ClinPred		0.018	T
GERP RS		4.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.23
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200704265; hg19: chr9-139731827; COSMIC: COSV61036329; COSMIC: COSV61036329;