NM_016573.4:c.2686G>A

Variant names:

• chr19-19630190-C-T
• rs1363796433
• NM_016573.4:c.2686G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016573.4(GMIP):​c.2686G>A​(p.Glu896Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000812 in 1,601,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: GMIP NM_016573.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17815718).

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.2686G>A	p.Glu896Lys	missense	Exon 21 of 21	NP_057657.2	Q9P107-1
	GMIP	NM_001288999.2		c.2608G>A	p.Glu870Lys	missense	Exon 20 of 20	NP_001275928.1	Q9P107-2
	GMIP	NM_001288998.2		c.2599G>A	p.Glu867Lys	missense	Exon 20 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.2686G>A	p.Glu896Lys	missense	Exon 21 of 21	ENSP00000203556.3	Q9P107-1
	GMIP	ENST00000587238.5	TSL:1	c.2608G>A	p.Glu870Lys	missense	Exon 20 of 20	ENSP00000467054.1	Q9P107-2
	GMIP	ENST00000940889.1		c.2662G>A	p.Glu888Lys	missense	Exon 21 of 21	ENSP00000610948.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 242772 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: 0.00000828 AC: 12 AN: 1449470 Hom.: 0 Cov.: 33 AF XY: 0.00000835 AC XY: 6 AN XY: 718906

African (AFR) AF: 0.00 AC: 0 AN: 33270

American (AMR) AF: 0.0000227 AC: 1 AN: 43996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25592

East Asian (EAS) AF: 0.00 AC: 0 AN: 39384

South Asian (SAS) AF: 0.00 AC: 0 AN: 85392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000997 AC: 11 AN: 1103294

Other (OTH) AF: 0.00 AC: 0 AN: 59750

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

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	0.12
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.026	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.11
Sift	Uncertain	0.018	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.29
MutPred		0.39		Gain of methylation at E896 (P = 0.0026)
MVP		0.45
MPC		0.96
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.092
gMVP		0.51
Mutation Taster		=84/16	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: rs1363796433; hg19: chr19-19740999; COSMIC: COSV52556950; COSMIC: COSV52556950;