2-172736006-A-T

Variant names:

• chr2-172736006-A-T
• rs1375983141
• NM_007023.4:c.23A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007023.4(RAPGEF4):​c.23A>T​(p.His8Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000753 in 1,327,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H8Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: RAPGEF4 NM_007023.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.61
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3937824).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007023.4. 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
	RAPGEF4	NM_007023.4	MANE Select	c.23A>T	p.His8Leu	missense	Exon 1 of 31	NP_008954.2	Q8WZA2-1
	RAPGEF4	NM_001375865.1		c.23A>T	p.His8Leu	missense	Exon 1 of 31	NP_001362794.1
	RAPGEF4	NM_001375866.1		c.23A>T	p.His8Leu	missense	Exon 1 of 30	NP_001362795.1	X5D7N4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPGEF4	ENST00000397081.8	TSL:1 MANE Select	c.23A>T	p.His8Leu	missense	Exon 1 of 31	ENSP00000380271.3	Q8WZA2-1
	RAPGEF4	ENST00000409036.5	TSL:5	c.23A>T	p.His8Leu	missense	Exon 1 of 28	ENSP00000387104.1	E9PB94
	RAPGEF4-AS1	ENST00000435328.1	TSL:1	n.81+120T>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.53e-7 AC: 1 AN: 1327948 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 655112

African (AFR) AF: 0.00 AC: 0 AN: 26530

American (AMR) AF: 0.00 AC: 0 AN: 27316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22836

East Asian (EAS) AF: 0.00 AC: 0 AN: 27412

South Asian (SAS) AF: 0.00 AC: 0 AN: 73712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4064

European-Non Finnish (NFE) AF: 9.56e-7 AC: 1 AN: 1045812

Other (OTH) AF: 0.00 AC: 0 AN: 54096

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.0050	B
Vest4		0.55
MutPred		0.34		Gain of helix (P = 0.0117)
MVP		0.38
MPC		0.78
ClinPred		0.78	D
GERP RS		3.0
PromoterAI		0.21	Neutral
Varity_R		0.38
gMVP		0.69
Mutation Taster		=90/10	polymorphism

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

dbSNP: rs1375983141; hg19: chr2-173600734;