10-43199177-G-T

Position:

• chr10-43199177-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145313.4(RASGEF1A):​c.867C>A​(p.His289Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RASGEF1A NM_145313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.181

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08133191).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGEF1A	NM_145313.4	c.867C>A	p.His289Gln	missense_variant	8/13	ENST00000395810.6	NP_660356.2
RASGEF1A	NM_001282862.2	c.891C>A	p.His297Gln	missense_variant	8/13		NP_001269791.1
RASGEF1A	XM_005271809.4	c.627C>A	p.His209Gln	missense_variant	7/12		XP_005271866.1
RASGEF1A	XM_011539500.3	c.627C>A	p.His209Gln	missense_variant	7/12		XP_011537802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASGEF1A	ENST00000395810.6	c.867C>A	p.His289Gln	missense_variant	8/13	1	NM_145313.4	ENSP00000379155	A1
RASGEF1A	ENST00000374459.5	c.891C>A	p.His297Gln	missense_variant	8/13	2		ENSP00000363583	P4
RASGEF1A	ENST00000395809.5	c.867C>A	p.His289Gln	missense_variant	8/13	2		ENSP00000379154	A1
RASGEF1A	ENST00000374455.2	c.573C>A	p.His191Gln	missense_variant	6/6	5		ENSP00000363579

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458986 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Sep 22, 2022

The c.867C>A (p.H289Q) alteration is located in exon 7 (coding exon 7) of the RASGEF1A gene. This alteration results from a C to A substitution at nucleotide position 867, causing the histidine (H) at amino acid position 289 to be replaced by a glutamine (Q). 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	Benign	0.098
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.7
DANN	Benign	0.73
DEOGEN2	Benign	0.0082	.;T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.80	T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.081	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.42	.;N;N
MutationTaster	Benign	0.63	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.089
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.14
MutPred		0.36		.;Gain of methylation at K286 (P = 0.0726);Gain of methylation at K286 (P = 0.0726);
MVP		0.10
MPC		0.73
ClinPred		0.048	T
GERP RS		-3.1
Varity_R		0.028
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-43694625;