22-41249337-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002883.4(RANGAP1):c.1687G>A(p.Val563Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,602,006 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: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: RANGAP1 NM_002883.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.65

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.054968446).
• BP6: Variant 22-41249337-C-T is Benign according to our data. Variant chr22-41249337-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2491150.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANGAP1	NM_002883.4	c.1687G>A	p.Val563Met	missense_variant	15/16	ENST00000356244.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANGAP1	ENST00000356244.8	c.1687G>A	p.Val563Met	missense_variant	15/16	1	NM_002883.4	P1
RANGAP1	ENST00000405486.5	c.1687G>A	p.Val563Met	missense_variant	16/17	1		P1
RANGAP1	ENST00000455915.6	c.1687G>A	p.Val563Met	missense_variant	14/15	1		P1
RANGAP1	ENST00000705116.1	c.1687G>A	p.Val563Met	missense_variant	15/16			P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152270 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000415 AC: 10 AN: 240874 Hom.: 0 AF XY: 0.0000538 AC XY: 7 AN XY: 130114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.0000695

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1449618 Hom.: 0 Cov.: 30 AF XY: 0.0000181 AC XY: 13 AN XY: 719896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000457

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000253

Gnomad4 SAS exome AF: 0.0000474

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000543

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000262 AC: 4 AN: 152388 Hom.: 0 Cov.: 34 AF XY: 0.0000268 AC XY: 2 AN XY: 74520

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

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

Feb 28, 2023

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	0.16
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.17
Dann	Benign	0.57
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.055	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.18	N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.17	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.069	B;B;B
Vest4		0.17
MutPred		0.72		Loss of ubiquitination at K565 (P = 0.0709);Loss of ubiquitination at K565 (P = 0.0709);Loss of ubiquitination at K565 (P = 0.0709);
MVP		0.15
MPC		0.23
ClinPred		0.024	T
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.20

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: rs200464078; hg19: chr22-41645341;