2-172996521-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_007023.4(RAPGEF4):c.1546A>G(p.Ile516Val) variant causes a missense change. The variant allele was found at a frequency of 0.000965 in 1,586,500 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0056 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (8 hom.)
• Consequence: RAPGEF4 NM_007023.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.92

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039631426).
• BP6: Variant 2-172996521-A-G is Benign according to our data. Variant chr2-172996521-A-G is described in ClinVar as [Benign]. Clinvar id is 789707.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00559 (852/152362) while in subpopulation AFR AF= 0.0195 (810/41580). AF 95% confidence interval is 0.0184. There are 13 homozygotes in gnomad4. There are 408 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 845 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPGEF4	NM_007023.4	c.1546A>G	p.Ile516Val	missense_variant	16/31	ENST00000397081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPGEF4	ENST00000397081.8	c.1546A>G	p.Ile516Val	missense_variant	16/31	1	NM_007023.4	P1

Frequencies

GnomAD3 genomes AF: 0.00555 AC: 845 AN: 152244 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00123 AC: 272 AN: 221546 Hom.: 4 AF XY: 0.000986 AC XY: 119 AN XY: 120666

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.000820

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000403

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.000583

GnomAD4 exome AF: 0.000473 AC: 679 AN: 1434138 Hom.: 8 Cov.: 30 AF XY: 0.000424 AC XY: 302 AN XY: 713002

Gnomad4 AFR exome AF: 0.0184

Gnomad4 AMR exome AF: 0.000793

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000372

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000998

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.00559 AC: 852 AN: 152362 Hom.: 13 Cov.: 32 AF XY: 0.00548 AC XY: 408 AN XY: 74502

Gnomad4 AFR AF: 0.0195

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000941 Hom.: 3

Bravo AF: 0.00606

ESP6500AA AF: 0.0184 AC: 67

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.00181 AC: 219

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.098	T;.;.;.;.;T
Eigen	Benign	-0.098
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
MetaRNN	Benign	0.0040	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L;.;.;.;.;.
MutationTaster	Benign	0.88	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.17	N;N;N;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.27	T;T;T;T;D;T
Sift4G	Benign	0.079	T;T;T;T;T;T
Polyphen		0.0010	B;.;B;.;.;.
Vest4		0.077
MVP		0.19
MPC		0.29
ClinPred		0.052	T
GERP RS		3.4
Varity_R		0.048
gMVP		0.17

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: rs112722051; hg19: chr2-173861249;