2-172736006-A-G

Position:

• chr2-172736006-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_007023.4(RAPGEF4):​c.23A>G​(p.His8Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000158 in 1,327,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RAPGEF4 NM_007023.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61

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]

RAPGEF4-AS1 (HGNC:28081): (RAPGEF4 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2790716).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF4	NM_007023.4	c.23A>G	p.His8Arg	missense_variant	1/31	ENST00000397081.8	NP_008954.2
RAPGEF4-AS1	NR_026995.1	n.81+120T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF4	ENST00000397081.8	c.23A>G	p.His8Arg	missense_variant	1/31	1	NM_007023.4	ENSP00000380271	P1
RAPGEF4-AS1	ENST00000435328.1	n.81+120T>C		intron_variant, non_coding_transcript_variant		1
RAPGEF4	ENST00000409036.5	c.23A>G	p.His8Arg	missense_variant	1/28	5		ENSP00000387104
RAPGEF4	ENST00000484331.5	n.132+601A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000158 AC: 21 AN: 1327948 Hom.: 0 Cov.: 29 AF XY: 0.0000122 AC XY: 8 AN XY: 655112

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: 0.0000201

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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 16, 2021

The c.23A>G (p.H8R) alteration is located in exon 1 (coding exon 1) of the RAPGEF4 gene. This alteration results from a A to G substitution at nucleotide position 23, causing the histidine (H) at amino acid position 8 to be replaced by an arginine (R). 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	0.079
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.99	N;N
REVEL	Benign	0.082
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.0	B;B
Vest4		0.48
MutPred		0.33		Gain of MoRF binding (P = 0.0305);Gain of MoRF binding (P = 0.0305);
MVP		0.48
MPC		0.77
ClinPred		0.81	D
GERP RS		3.0
Varity_R		0.30
gMVP		0.69

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

LitVar

Other links and lift over

dbSNP: rs1375983141; hg19: chr2-173600734;