X-48981803-C-T

Variant names:

• chrX-48981803-C-T
• rs185201841
• NM_020137.5:c.1669G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_020137.5(GRIPAP1):​c.1669G>A​(p.Glu557Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000655 in 1,175,705 control chromosomes in the GnomAD database, including 1 homozygotes. There are 23 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000066 (1 hom. 22 hem.)
• Consequence: GRIPAP1 NM_020137.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.65
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10852456).
• BP6: Variant X-48981803-C-T is Benign according to our data. Variant chrX-48981803-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2429772.
• BS2: High Hemizygotes in GnomAdExome4 at 22 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020137.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIPAP1	NM_020137.5	MANE Select	c.1669G>A	p.Glu557Lys	missense	Exon 18 of 26	NP_064522.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIPAP1	ENST00000376423.8	TSL:1 MANE Select	c.1669G>A	p.Glu557Lys	missense	Exon 18 of 26	ENSP00000365606.5	Q4V328-1
	GRIPAP1	ENST00000900849.1		c.1744G>A	p.Glu582Lys	missense	Exon 19 of 28	ENSP00000570908.1
	GRIPAP1	ENST00000946827.1		c.1744G>A	p.Glu582Lys	missense	Exon 19 of 28	ENSP00000616886.1

Frequencies

GnomAD3 genomes AF: 0.0000624 AC: 7 AN: 112238 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00113

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000362 AC: 5 AN: 138176 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000473

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000658 AC: 70 AN: 1063417 Hom.: 1 Cov.: 30 AF XY: 0.0000648 AC XY: 22 AN XY: 339489

African (AFR) AF: 0.00 AC: 0 AN: 25568

American (AMR) AF: 0.00 AC: 0 AN: 31443

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18808

East Asian (EAS) AF: 0.00241 AC: 69 AN: 28641

South Asian (SAS) AF: 0.0000196 AC: 1 AN: 50974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4085

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 820791

Other (OTH) AF: 0.00 AC: 0 AN: 44893

GnomAD4 genome AF: 0.0000623 AC: 7 AN: 112288 Hom.: 0 Cov.: 24 AF XY: 0.0000290 AC XY: 1 AN XY: 34468

African (AFR) AF: 0.0000322 AC: 1 AN: 31030

American (AMR) AF: 0.00 AC: 0 AN: 10655

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00113 AC: 4 AN: 3535

South Asian (SAS) AF: 0.00 AC: 0 AN: 2737

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53115

Other (OTH) AF: 0.00 AC: 0 AN: 1523

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	-	1	Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.063	T
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.6
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	0.28	T
Polyphen		0.88	P
Vest4		0.37
MVP		0.47
ClinPred		0.32	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.14
gMVP		0.27
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs185201841; hg19: chrX-48838215;