19-19630276-C-A

Variant names:

• chr19-19630276-C-A
• rs199807296
• NM_016573.4:c.2600G>T

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.2600G>T​(p.Arg867Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,396,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R867H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GMIP NM_016573.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.77
• 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: 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=0.22015777).

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.2600G>T	p.Arg867Leu	missense	Exon 21 of 21	NP_057657.2	Q9P107-1
	GMIP	NM_001288999.2		c.2522G>T	p.Arg841Leu	missense	Exon 20 of 20	NP_001275928.1	Q9P107-2
	GMIP	NM_001288998.2		c.2513G>T	p.Arg838Leu	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.2600G>T	p.Arg867Leu	missense	Exon 21 of 21	ENSP00000203556.3	Q9P107-1
	GMIP	ENST00000587238.5	TSL:1	c.2522G>T	p.Arg841Leu	missense	Exon 20 of 20	ENSP00000467054.1	Q9P107-2
	GMIP	ENST00000940889.1		c.2576G>T	p.Arg859Leu	missense	Exon 21 of 21	ENSP00000610948.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396590 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 687268

African (AFR) AF: 0.00 AC: 0 AN: 31742

American (AMR) AF: 0.00 AC: 0 AN: 36780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21844

East Asian (EAS) AF: 0.00 AC: 0 AN: 39016

South Asian (SAS) AF: 0.00 AC: 0 AN: 76438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5448

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078400

Other (OTH) AF: 0.00 AC: 0 AN: 57348

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.34		Loss of MoRF binding (P = 0.0067)
MVP		0.52
MPC		1.1
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.28
gMVP		0.55
Mutation Taster		=60/40	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: rs199807296; hg19: chr19-19741085;