X-48981451-C-T

Position:

• chrX-48981451-C-T

Variant summary

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

The NM_020137.5(GRIPAP1):​c.1795G>A​(p.Gly599Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000888 in 112,646 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: GRIPAP1 NM_020137.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.15

Genes affected

GRIPAP1 (HGNC:18706): (GRIP1 associated protein 1) This gene encodes a guanine nucleotide exchange factor for the Ras family of small G proteins (RasGEF). The encoded protein interacts in a complex with glutamate receptor interacting protein 1 (GRIP1) and plays a role in the regulation of AMPA receptor function. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIPAP1	NM_020137.5	c.1795G>A	p.Gly599Arg	missense_variant	20/26	ENST00000376423.8	NP_064522.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIPAP1	ENST00000376423.8	c.1795G>A	p.Gly599Arg	missense_variant	20/26	1	NM_020137.5	ENSP00000365606	P3

Frequencies

GnomAD3 genomes AF: 0.00000888 AC: 1 AN: 112646 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34796

Gnomad AFR AF: 0.0000322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000888 AC: 1 AN: 112646 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34796

Gnomad4 AFR AF: 0.0000322

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

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

May 14, 2024

The c.1795G>A (p.G599R) alteration is located in exon 20 (coding exon 20) of the GRIPAP1 gene. This alteration results from a G to A substitution at nucleotide position 1795, causing the glycine (G) at amino acid position 599 to be replaced by an arginine (R). 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	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.059	.;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	2.0	.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
REVEL	Benign	0.19
Sift4G	Benign	0.13	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.59
MutPred		0.22		.;.;Gain of MoRF binding (P = 0.0211);
MVP		0.95
ClinPred		0.97	D
GERP RS		4.8
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.73
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373720668; hg19: chrX-48837863;