22-41249357-G-A

Position:

• chr22-41249357-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002883.4(RANGAP1):​c.1667C>T​(p.Ala556Val) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: RANGAP1 NM_002883.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.926

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10767192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANGAP1	NM_002883.4	c.1667C>T	p.Ala556Val	missense_variant	15/16	ENST00000356244.8	NP_002874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANGAP1	ENST00000356244.8	c.1667C>T	p.Ala556Val	missense_variant	15/16	1	NM_002883.4	ENSP00000348577.3
RANGAP1	ENST00000405486.5	c.1667C>T	p.Ala556Val	missense_variant	16/17	1		ENSP00000385866.1
RANGAP1	ENST00000455915.6	c.1667C>T	p.Ala556Val	missense_variant	14/15	1		ENSP00000401470.2
RANGAP1	ENST00000705116.1	c.1667C>T	p.Ala556Val	missense_variant	15/16			ENSP00000516069.1

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

Nov 24, 2024

The c.1667C>T (p.A556V) alteration is located in exon 15 (coding exon 14) of the RANGAP1 gene. This alteration results from a C to T substitution at nucleotide position 1667, causing the alanine (A) at amino acid position 556 to be replaced by a valine (V). 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	0.080
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.77
DEOGEN2	Benign	0.27	T;T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.76	.;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.059
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.92	T;T;T
Polyphen		0.016	B;B;B
Vest4		0.19
MutPred		0.77		Gain of methylation at K553 (P = 0.0911);Gain of methylation at K553 (P = 0.0911);Gain of methylation at K553 (P = 0.0911);
MVP		0.14
MPC		0.23
ClinPred		0.090	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-41645361;