22-41254476-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_002883.4(RANGAP1):c.1092G>C(p.Glu364Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RANGAP1 NM_002883.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.643

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04086086).
• BP6: Variant 22-41254476-C-G is Benign according to our data. Variant chr22-41254476-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2266757.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANGAP1	NM_002883.4	c.1092G>C	p.Glu364Asp	missense_variant	11/16	ENST00000356244.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANGAP1	ENST00000356244.8	c.1092G>C	p.Glu364Asp	missense_variant	11/16	1	NM_002883.4	P1
RANGAP1	ENST00000405486.5	c.1092G>C	p.Glu364Asp	missense_variant	12/17	1		P1
RANGAP1	ENST00000455915.6	c.1092G>C	p.Glu364Asp	missense_variant	10/15	1		P1
RANGAP1	ENST00000705116.1	c.1092G>C	p.Glu364Asp	missense_variant	11/16			P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445456 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 718298

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.91
Dann	Benign	0.071
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.48	N
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.041	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.085	N;N;N
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.0	N;N;N
REVEL	Benign	0.028
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.68	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.19
MutPred		0.37		Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP		0.19
MPC		0.20
ClinPred		0.022	T
GERP RS		0.76
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.9
Varity_R		0.020
gMVP		0.026

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: rs1601604945; hg19: chr22-41650480;