chr1-156066103-C-G

Position:

• chr1-156066103-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020387.4(RAB25):​c.236C>G​(p.Ser79Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S79L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB25 NM_020387.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

Genes affected

RAB25 (HGNC:18238): (RAB25, member RAS oncogene family) The protein encoded by this gene is a member of the RAS superfamily of small GTPases. The encoded protein is involved in membrane trafficking and cell survival. This gene has been found to be a tumor suppressor and an oncogene, depending on the context. Two variants, one protein-coding and the other not, have been found for this gene. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB25	NM_020387.4	c.236C>G	p.Ser79Trp	missense_variant	2/5	ENST00000361084.10
RAB25	NR_133653.2	n.285-2167C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB25	ENST00000361084.10	c.236C>G	p.Ser79Trp	missense_variant	2/5	1	NM_020387.4	P1
RAB25	ENST00000463614.1	n.448C>G		non_coding_transcript_exon_variant	2/2	2
RAB25	ENST00000473336.5	n.62-2167C>G		intron_variant, non_coding_transcript_variant		2
RAB25	ENST00000487325.5	n.239-2167C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.236C>G (p.S79W) alteration is located in exon 2 (coding exon 2) of the RAB25 gene. This alteration results from a C to G substitution at nucleotide position 236, causing the serine (S) at amino acid position 79 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.88
MutPred		0.67		Gain of MoRF binding (P = 0.0378);
MVP		0.95
MPC		1.0
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-156035894;