2-173001343-C-A

Variant summary

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

The NM_007023.4(RAPGEF4):c.1657C>A(p.His553Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAPGEF4 NM_007023.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.67

Genes affected

RAPGEF4 (HGNC:16626): (Rap guanine nucleotide exchange factor 4) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of neurotransmitter receptor localization to postsynaptic specialization membrane and regulation of postsynapse organization. Predicted to act upstream of or within adenylate cyclase-activating G protein-coupled receptor signaling pathway; regulation of exocytosis; and secretion by cell. Predicted to be located in plasma membrane. Predicted to be active in glutamatergic synapse; hippocampal mossy fiber to CA3 synapse; and postsynaptic density. Implicated in autistic disorder. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPGEF4	NM_007023.4	c.1657C>A	p.His553Asn	missense_variant, splice_region_variant	17/31	ENST00000397081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPGEF4	ENST00000397081.8	c.1657C>A	p.His553Asn	missense_variant, splice_region_variant	17/31	1	NM_007023.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 16, 2023

The c.1657C>A (p.H553N) alteration is located in exon 17 (coding exon 17) of the RAPGEF4 gene. This alteration results from a C to A substitution at nucleotide position 1657, causing the histidine (H) at amino acid position 553 to be replaced by an asparagine (N). 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	0.21
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Benign	0.32	T;.;.;.;.;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D
REVEL	Benign	0.27
Sift	Benign	0.13	T;T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T;T
Polyphen		0.0030	B;.;B;.;.;.
Vest4		0.87
MutPred		0.55		Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);.;.;.;.;
MVP		0.75
MPC		0.44
ClinPred		0.89	D
GERP RS		5.9
Varity_R		0.30
gMVP		0.41

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: rs1693897304; hg19: chr2-173866071;