9-82992952-T-G

Variant names:

• chr9-82992952-T-G
• rs1053162513
• NM_152573.4:c.1994A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152573.4(RASEF):​c.1994A>C​(p.Glu665Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: RASEF NM_152573.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71
• Publications: 0 publications found

Genes affected

RASEF (HGNC:26464): (RAS and EF-hand domain containing) This gene is a member of the Rab family of GTPases that are involved in regulation of membrane traffic. The encoded protein contains an N-terminal EF-hand domain, a coiled-coil motif and a C-terminal Rab domain. A potential role as tumor suppressor has been indicated for this gene. [provided by RefSeq, Nov 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23873752).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152573.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASEF	NM_152573.4	MANE Select	c.1994A>C	p.Glu665Ala	missense	Exon 15 of 17	NP_689786.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASEF	ENST00000376447.4	TSL:1 MANE Select	c.1994A>C	p.Glu665Ala	missense	Exon 15 of 17	ENSP00000365630.3	Q8IZ41-1
	RASEF	ENST00000928035.1		c.1979A>C	p.Glu660Ala	missense	Exon 15 of 17	ENSP00000598094.1
	RASEF	ENST00000873431.1		c.1925A>C	p.Glu642Ala	missense	Exon 14 of 16	ENSP00000543490.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152050 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74252

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.7
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.11
Sift	Uncertain	0.022	D
Sift4G	Benign	0.17	T
Polyphen		0.010	B
Vest4		0.18
MutPred		0.52		Gain of catalytic residue at E665 (P = 0.0558)
MVP		0.59
MPC		0.17
ClinPred		0.63	D
GERP RS		4.5
Varity_R		0.24
gMVP		0.42
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs1053162513; hg19: chr9-85607867;