16-282693-C-T

Variant names:

• chr16-282693-C-T
• rs751743144
• NM_001176.4:c.557C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001176.4(ARHGDIG):​c.557C>T​(p.Ala186Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,601,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: ARHGDIG NM_001176.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.768
• Publications: 1 publications found

Genes affected

ARHGDIG (HGNC:680): (Rho GDP dissociation inhibitor gamma) The GDP-dissociation inhibitors (GDIs) play a primary role in modulating the activation of GTPases by inhibiting the exchange of GDP for GTP. See ARHGDIB (MIM 602843).[supplied by OMIM, Nov 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001176.4. 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
	ARHGDIG	NM_001176.4	MANE Select	c.557C>T	p.Ala186Val	missense	Exon 6 of 6	NP_001167.2	Q99819

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGDIG	ENST00000219409.8	TSL:1 MANE Select	c.557C>T	p.Ala186Val	missense	Exon 6 of 6	ENSP00000219409.3	Q99819
	ARHGDIG	ENST00000856700.1		c.599C>T	p.Ala200Val	missense	Exon 6 of 6	ENSP00000526759.1
	ARHGDIG	ENST00000965841.1		c.458C>T	p.Ala153Val	missense	Exon 6 of 6	ENSP00000635900.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152068 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: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000595 AC: 14 AN: 235370 AF XY: 0.0000627

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000601

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000104

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000187 AC: 271 AN: 1449052 Hom.: 0 Cov.: 36 AF XY: 0.000183 AC XY: 132 AN XY: 719470

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.0000457 AC: 2 AN: 43750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25396

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 84272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.000233 AC: 258 AN: 1105766

Other (OTH) AF: 0.000167 AC: 10 AN: 59858

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74280

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67968

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

Alfa AF: 0.0000931 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

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	0.081
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.77
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.20
Sift	Benign	0.053	T
Sift4G	Uncertain	0.025	D
Polyphen		0.93	P
Vest4		0.15
MutPred		0.88		Loss of disorder (P = 0.0803)
MVP		0.46
MPC		0.075
ClinPred		0.38	T
GERP RS		4.1
PromoterAI		0.032	Neutral
Varity_R		0.12
gMVP		0.48
Mutation Taster		=75/25	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: rs751743144; hg19: chr16-332693; COSMIC: COSV51988995; COSMIC: COSV51988995;