19-19633918-G-A

Variant names:

• chr19-19633918-G-A
• rs1235711124
• NM_016573.4:c.2357C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016573.4(GMIP):​c.2357C>T​(p.Pro786Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,542,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: GMIP NM_016573.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.101
• Publications: 1 publications found

Genes affected

GMIP (HGNC:24852): (GEM interacting protein) This gene encodes a member of the ARHGAP family of Rho/Rac/Cdc42-like GTPase activating proteins. The encoded protein interacts with the Ras-related protein Gem through its N-terminal domain. Separately, it interacts with RhoA through a RhoGAP domain, and stimulates RhoA-dependent GTPase activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06700227).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016573.4. 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
	GMIP	NM_016573.4	MANE Select	c.2357C>T	p.Pro786Leu	missense	Exon 19 of 21	NP_057657.2	Q9P107-1
	GMIP	NM_001288999.2		c.2279C>T	p.Pro760Leu	missense	Exon 18 of 20	NP_001275928.1	Q9P107-2
	GMIP	NM_001288998.2		c.2270C>T	p.Pro757Leu	missense	Exon 18 of 20	NP_001275927.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMIP	ENST00000203556.9	TSL:1 MANE Select	c.2357C>T	p.Pro786Leu	missense	Exon 19 of 21	ENSP00000203556.3	Q9P107-1
	GMIP	ENST00000587238.5	TSL:1	c.2279C>T	p.Pro760Leu	missense	Exon 18 of 20	ENSP00000467054.1	Q9P107-2
	GMIP	ENST00000940889.1		c.2333C>T	p.Pro778Leu	missense	Exon 19 of 21	ENSP00000610948.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151172 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 189914 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 20 AN: 1390832 Hom.: 0 Cov.: 32 AF XY: 0.00000878 AC XY: 6 AN XY: 683106

African (AFR) AF: 0.0000314 AC: 1 AN: 31824

American (AMR) AF: 0.00 AC: 0 AN: 36952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22282

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38606

South Asian (SAS) AF: 0.0000385 AC: 3 AN: 77892

European-Finnish (FIN) AF: 0.0000201 AC: 1 AN: 49774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5152

European-Non Finnish (NFE) AF: 0.0000121 AC: 13 AN: 1071166

Other (OTH) AF: 0.0000175 AC: 1 AN: 57184

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151172 Hom.: 0 Cov.: 26 AF XY: 0.0000136 AC XY: 1 AN XY: 73776

African (AFR) AF: 0.00 AC: 0 AN: 41034

American (AMR) AF: 0.00 AC: 0 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67802

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.59
DANN	Benign	0.59
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.10
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.023
Sift	Benign	0.78	T
Sift4G	Benign	0.22	T
Polyphen		0.0020	B
Vest4		0.27
MutPred		0.22		Loss of glycosylation at P786 (P = 0.0224)
MVP		0.21
MPC		0.28
ClinPred		0.033	T
GERP RS		0.089
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.16
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1235711124; hg19: chr19-19744727; COSMIC: COSV52557051; COSMIC: COSV52557051;