22-41252945-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/21 in silico tools predict 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

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

Verdict is Uncertain_significance. Variant got 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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANGAP1	NM_002883.4	c.1307C>G	p.Thr436Ser	missense_variant	Exon 12 of 16	ENST00000356244.8	NP_002874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RANGAP1	ENST00000356244.8	c.1307C>G	p.Thr436Ser	missense_variant	Exon 12 of 16	1	NM_002883.4	ENSP00000348577.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1307C>G (p.T436S) alteration is located in exon 12 (coding exon 11) of the RANGAP1 gene. This alteration results from a C to G substitution at nucleotide position 1307, causing the threonine (T) at amino acid position 436 to be replaced by a serine (S). 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	0.10
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T;T;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;T;T
MetaSVM	Uncertain	0.056	D
MutationAssessor	Benign	1.4	L;L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.50	N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.037	B;B;B
Vest4		0.26
MutPred		0.59		Loss of glycosylation at S435 (P = 0.0605);Loss of glycosylation at S435 (P = 0.0605);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-41648949;