NM_002883.4:c.1307C>G

Variant names:

• chr22-41252945-G-C
• NM_002883.4:c.1307C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_002883.4(RANGAP1):​c.1307C>G​(p.Thr436Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RANGAP1 NM_002883.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.74
• Publications: 0 publications found

Genes affected

RANGAP1 (HGNC:9854): (Ran GTPase activating protein 1) This gene encodes a protein that associates with the nuclear pore complex and participates in the regulation of nuclear transport. The encoded protein interacts with Ras-related nuclear protein 1 (RAN) and regulates guanosine triphosphate (GTP)-binding and exchange. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

MIR6889 (HGNC:50014): (microRNA 6889) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a modified_residue Phosphothreonine (size 0) in uniprot entity RAGP1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27464426).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002883.4. 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
	RANGAP1	NM_002883.4	MANE Select	c.1307C>G	p.Thr436Ser	missense	Exon 12 of 16	NP_002874.1	P46060
	RANGAP1	NM_001278651.2		c.1307C>G	p.Thr436Ser	missense	Exon 13 of 17	NP_001265580.1	P46060
	RANGAP1	NM_001317930.2		c.1307C>G	p.Thr436Ser	missense	Exon 12 of 16	NP_001304859.1	P46060

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANGAP1	ENST00000356244.8	TSL:1 MANE Select	c.1307C>G	p.Thr436Ser	missense	Exon 12 of 16	ENSP00000348577.3	P46060
	RANGAP1	ENST00000405486.5	TSL:1	c.1307C>G	p.Thr436Ser	missense	Exon 13 of 17	ENSP00000385866.1	P46060
	RANGAP1	ENST00000455915.6	TSL:1	c.1307C>G	p.Thr436Ser	missense	Exon 11 of 15	ENSP00000401470.2	P46060

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.0072
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.056	D
MutationAssessor	Benign	1.4	L
PhyloP100		9.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.50	N
REVEL	Uncertain	0.45
Sift	Benign	0.47	T
Sift4G	Benign	0.64	T
Polyphen		0.037	B
Vest4		0.26
MutPred		0.59		Loss of glycosylation at S435 (P = 0.0605)
MVP		0.72
MPC		0.20
ClinPred		0.84	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.044
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr22-41648949;