19-19634670-C-T

Variant names:

• chr19-19634670-C-T
• rs12003
• NM_016573.4:c.1921G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_016573.4(GMIP):​c.1921G>A​(p.Asp641Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 1,611,504 control chromosomes in the GnomAD database, including 1,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.027 (91 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1007 hom.)
• Consequence: GMIP NM_016573.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 14 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031639338).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0268 (4069/152032) while in subpopulation NFE AF = 0.0363 (2466/67964). AF 95% confidence interval is 0.0351. There are 91 homozygotes in GnomAd4. There are 2000 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 91 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMIP	NM_016573.4	c.1921G>A	p.Asp641Asn	missense_variant	Exon 18 of 21	ENST00000203556.9	NP_057657.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMIP	ENST00000203556.9	c.1921G>A	p.Asp641Asn	missense_variant	Exon 18 of 21	1	NM_016573.4	ENSP00000203556.3
GMIP	ENST00000587238.5	c.1843G>A	p.Asp615Asn	missense_variant	Exon 17 of 20	1		ENSP00000467054.1
GMIP	ENST00000586269.1	n.453+122G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0268 AC: 4070 AN: 151914 Hom.: 91 Cov.: 32

Gnomad AFR AF: 0.00610

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0718

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0654

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0363

Gnomad OTH AF: 0.0221

GnomAD2 exomes AF: 0.0298 AC: 7454 AN: 249804 AF XY: 0.0307

Gnomad AFR exome AF: 0.00512

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.0621

Gnomad EAS exome AF: 0.000382

Gnomad FIN exome AF: 0.0634

Gnomad NFE exome AF: 0.0368

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0352 AC: 51387 AN: 1459472 Hom.: 1007 Cov.: 34 AF XY: 0.0350 AC XY: 25373 AN XY: 725758

African (AFR) AF: 0.00617 AC: 206 AN: 33404

American (AMR) AF: 0.0148 AC: 657 AN: 44354

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 1633 AN: 26020

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39646

South Asian (SAS) AF: 0.0173 AC: 1494 AN: 86236

European-Finnish (FIN) AF: 0.0613 AC: 3272 AN: 53344

Middle Eastern (MID) AF: 0.0319 AC: 183 AN: 5740

European-Non Finnish (NFE) AF: 0.0378 AC: 42008 AN: 1110472

Other (OTH) AF: 0.0320 AC: 1928 AN: 60256

GnomAD4 genome AF: 0.0268 AC: 4069 AN: 152032 Hom.: 91 Cov.: 32 AF XY: 0.0269 AC XY: 2000 AN XY: 74312

African (AFR) AF: 0.00608 AC: 252 AN: 41458

American (AMR) AF: 0.0181 AC: 277 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0718 AC: 249 AN: 3468

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5154

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4818

European-Finnish (FIN) AF: 0.0654 AC: 691 AN: 10572

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0363 AC: 2466 AN: 67964

Other (OTH) AF: 0.0218 AC: 46 AN: 2106

Alfa AF: 0.0316 Hom.: 266

Bravo AF: 0.0225

TwinsUK AF: 0.0423 AC: 157

ALSPAC AF: 0.0358 AC: 138

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0350 AC: 301

ExAC AF: 0.0287 AC: 3482

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.0346

EpiControl AF: 0.0330

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.81	T;D
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.11	N;.
PhyloP100		1.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.3	N;.
REVEL	Benign	0.066
Sift	Benign	0.77	T;.
Sift4G	Benign	0.66	T;T
Polyphen		0.038	B;.
Vest4		0.056
MPC		0.28
ClinPred		0.0027	T
GERP RS		2.5
Varity_R		0.066
gMVP		0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs12003; hg19: chr19-19745479; COSMIC: COSV52559395; COSMIC: COSV52559395;