chrX-48981829-T-C

Position:

• chrX-48981829-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_020137.5(GRIPAP1):​c.1643A>G​(p.Lys548Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,060,438 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000033 (0 hom. 10 hem.)
• Consequence: GRIPAP1 NM_020137.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.301

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.066055685).
• BS2: High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIPAP1	NM_020137.5	c.1643A>G	p.Lys548Arg	missense_variant	18/26	ENST00000376423.8	NP_064522.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIPAP1	ENST00000376423.8	c.1643A>G	p.Lys548Arg	missense_variant	18/26	1	NM_020137.5	ENSP00000365606	P3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.0000330 AC: 35 AN: 1060438 Hom.: 0 Cov.: 30 AF XY: 0.0000291 AC XY: 10 AN XY: 343344

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: 0.0000426

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

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

Mar 15, 2024

The c.1643A>G (p.K548R) alteration is located in exon 18 (coding exon 18) of the GRIPAP1 gene. This alteration results from a A to G substitution at nucleotide position 1643, causing the lysine (K) at amino acid position 548 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	Benign	0.065
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	.;T;T
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.066	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	.;.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	.;.;N
Sift	Uncertain	0.014	.;.;D
Sift4G	Benign	0.54	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.11
MutPred		0.11		.;.;Loss of ubiquitination at K548 (P = 0.0034);
MVP		0.15
ClinPred		0.087	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.087
gMVP		0.062

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chrX-48838241;