22-41249429-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002883.4(RANGAP1):c.1595T>C(p.Ile532Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: RANGAP1 NM_002883.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30146673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANGAP1	NM_002883.4	c.1595T>C	p.Ile532Thr	missense_variant	15/16	ENST00000356244.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANGAP1	ENST00000356244.8	c.1595T>C	p.Ile532Thr	missense_variant	15/16	1	NM_002883.4	P1
RANGAP1	ENST00000405486.5	c.1595T>C	p.Ile532Thr	missense_variant	16/17	1		P1
RANGAP1	ENST00000455915.6	c.1595T>C	p.Ile532Thr	missense_variant	14/15	1		P1
RANGAP1	ENST00000705116.1	c.1595T>C	p.Ile532Thr	missense_variant	15/16			P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

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

Jan 23, 2024

The c.1595T>C (p.I532T) alteration is located in exon 15 (coding exon 14) of the RANGAP1 gene. This alteration results from a T to C substitution at nucleotide position 1595, causing the isoleucine (I) at amino acid position 532 to be replaced by a threonine (T). 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	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	25
Dann	Benign	0.91
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.083
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	0.82	D;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.41	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.091	B;B;B
Vest4		0.48
MutPred		0.71		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP		0.29
MPC		0.30
ClinPred		0.44	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.17

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: rs939862654; hg19: chr22-41645433;