X-16123970-G-C

Position:

• chrX-16123970-G-C

Variant summary

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

The NM_005314.3(GRPR):​c.17G>C​(p.Cys6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000677 in 1,207,272 control chromosomes in the GnomAD database, including 2 homozygotes. There are 311 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., 21 hem., cov: 23)
  • Exomes 𝑓: 0.00068 (2 hom. 290 hem.)
• Consequence: GRPR NM_005314.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.42

Genes affected

GRPR (HGNC:4609): (gastrin releasing peptide receptor) Gastrin-releasing peptide (GRP) regulates numerous functions of the gastrointestinal and central nervous systems, including release of gastrointestinal hormones, smooth muscle cell contraction, and epithelial cell proliferation and is a potent mitogen for neoplastic tissues. The effects of GRP are mediated through the gastrin-releasing peptide receptor. This receptor is a glycosylated, 7-transmembrane G-protein coupled receptor that activates the phospholipase C signaling pathway. The receptor is aberrantly expressed in numerous cancers such as those of the lung, colon, and prostate. An individual with autism and multiple exostoses was found to have a balanced translocation between chromosome 8 and a chromosome X breakpoint located within the gastrin-releasing peptide receptor gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00465551).
• BP6: Variant X-16123970-G-C is Benign according to our data. Variant chrX-16123970-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 721453.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 21 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRPR	NM_005314.3	c.17G>C	p.Cys6Ser	missense_variant	1/3	ENST00000380289.3	NP_005305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRPR	ENST00000380289.3	c.17G>C	p.Cys6Ser	missense_variant	1/3	1	NM_005314.3	ENSP00000369643.2

Frequencies

GnomAD3 genomes AF: 0.000680 AC: 76 AN: 111822 Hom.: 0 Cov.: 23 AF XY: 0.000647 AC XY: 22 AN XY: 33996

Gnomad AFR AF: 0.0000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00134

GnomAD3 exomes AF: 0.000882 AC: 161 AN: 182591 Hom.: 1 AF XY: 0.00121 AC XY: 81 AN XY: 67163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.000936

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00178

Gnomad FIN exome AF: 0.000195

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000677 AC: 742 AN: 1095397 Hom.: 2 Cov.: 29 AF XY: 0.000804 AC XY: 290 AN XY: 360907

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00111

Gnomad4 ASJ exome AF: 0.000826

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00183

Gnomad4 FIN exome AF: 0.0000996

Gnomad4 NFE exome AF: 0.000642

Gnomad4 OTH exome AF: 0.000717

GnomAD4 genome AF: 0.000670 AC: 75 AN: 111875 Hom.: 0 Cov.: 23 AF XY: 0.000617 AC XY: 21 AN XY: 34059

Gnomad4 AFR AF: 0.0000650

Gnomad4 AMR AF: 0.000189

Gnomad4 ASJ AF: 0.00114

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00338

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.00132

Alfa AF: 0.000727 Hom.: 7

Bravo AF: 0.000612

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00149 AC: 10

ExAC AF: 0.00103 AC: 125

EpiCase AF: 0.00267

EpiControl AF: 0.00178

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 03, 2018

- -

GRPR-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.076	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.56	N
REVEL	Benign	0.090
Sift	Benign	0.15	T
Sift4G	Benign	0.84	T
Polyphen		0.035	B
Vest4		0.034
MutPred		0.42		Gain of disorder (P = 0.0012);
MVP		0.85
MPC		0.42
ClinPred		0.018	T
GERP RS		4.7
Varity_R		0.29
gMVP		0.63

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: rs75623611; hg19: chrX-16142093; COSMIC: COSV66669476;