chr10-43203338-C-A

Variant names:

• chr10-43203338-C-A
• NM_145313.4:c.281G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_145313.4(RASGEF1A):​c.281G>T​(p.Cys94Phe) variant causes a missense change. 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RASGEF1A NM_145313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76
• Publications: 0 publications found

Genes affected

RASGEF1A (HGNC:24246): (RasGEF domain family member 1A) Enables guanyl-nucleotide exchange factor activity. Involved in cell migration and positive regulation of Ras protein signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145313.4. 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
	RASGEF1A	NM_145313.4	MANE Select	c.281G>T	p.Cys94Phe	missense	Exon 3 of 13	NP_660356.2	Q8N9B8-1
	RASGEF1A	NM_001282862.2		c.305G>T	p.Cys102Phe	missense	Exon 3 of 13	NP_001269791.1	Q8N9B8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGEF1A	ENST00000395810.6	TSL:1 MANE Select	c.281G>T	p.Cys94Phe	missense	Exon 3 of 13	ENSP00000379155.1	Q8N9B8-1
	RASGEF1A	ENST00000954344.1		c.281G>T	p.Cys94Phe	missense	Exon 3 of 13	ENSP00000624403.1
	RASGEF1A	ENST00000374459.5	TSL:2	c.305G>T	p.Cys102Phe	missense	Exon 3 of 13	ENSP00000363583.1	Q8N9B8-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1426782 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 706490

African (AFR) AF: 0.00 AC: 0 AN: 32830

American (AMR) AF: 0.00 AC: 0 AN: 40352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25438

East Asian (EAS) AF: 0.00 AC: 0 AN: 38100

South Asian (SAS) AF: 0.00 AC: 0 AN: 81820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5150

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094676

Other (OTH) AF: 0.00 AC: 0 AN: 58978

GnomAD4 genome Cov.: 32

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	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.076
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.31
Sift	Benign	0.049	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.11	B
Vest4		0.80
MutPred		0.69		Gain of ubiquitination at K98 (P = 0.102)
MVP		0.73
MPC		1.2
ClinPred		0.93	D
GERP RS		3.5
Varity_R		0.65
gMVP		0.71
Mutation Taster		=49/51	disease causing

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

hg19: chr10-43698786;