chrX-48981820-C-T

Position:

• chrX-48981820-C-T

Variant summary

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

The NM_020137.5(GRIPAP1):​c.1652G>A​(p.Arg551Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,062,236 control chromosomes in the GnomAD database, including 1 homozygotes. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000075 (1 hom. 2 hem.)
• Consequence: GRIPAP1 NM_020137.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.806

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06092587).
• BP6: Variant X-48981820-C-T is Benign according to our data. Variant chrX-48981820-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3102581.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIPAP1	NM_020137.5	c.1652G>A	p.Arg551Gln	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.1652G>A	p.Arg551Gln	missense_variant	18/26	1	NM_020137.5	ENSP00000365606	P3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000753 AC: 8 AN: 1062236 Hom.: 1 Cov.: 30 AF XY: 0.00000583 AC XY: 2 AN XY: 342780

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: 0.00000608

Gnomad4 OTH exome AF: 0.0000670

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000175 AC: 2

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 12, 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	0.055
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.92
DANN	Benign	0.95
DEOGEN2	Benign	0.0052	.;T;T
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	.;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.91	T;T;T
Polyphen		0.0010	.;.;B
Vest4		0.074
MutPred		0.11		.;.;Loss of helix (P = 0.0068);
MVP		0.32
ClinPred		0.18	T
GERP RS		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.040

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs782363296; hg19: chrX-48838232;