19-1085691-G-A

Variant names:

• chr19-1085691-G-A
• rs149960692
• NM_012292.5:c.3096G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_012292.5(ARHGAP45):​c.3096G>A​(p.Ser1032Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,590,752 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (7 hom., cov: 31)
  • Exomes 𝑓: 0.00078 (12 hom.)
• Consequence: ARHGAP45 NM_012292.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.77
• Publications: 0 publications found

Genes affected

ARHGAP45 (HGNC:17102): (Rho GTPase activating protein 45) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

POLR2E (HGNC:9192): (RNA polymerase II, I and III subunit E) This gene encodes the fifth largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. This subunit is shared by the other two DNA-directed RNA polymerases and is present in two-fold molar excess over the other polymerase subunits. An interaction between this subunit and a hepatitis virus transactivating protein has been demonstrated, suggesting that interaction between transcriptional activators and the polymerase can occur through this subunit. A pseudogene is located on chromosome 11. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-1085691-G-A is Benign according to our data. Variant chr19-1085691-G-A is described in ClinVar as Benign. ClinVar VariationId is 717572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00722 (1086/150314) while in subpopulation AFR AF = 0.0251 (1029/41002). AF 95% confidence interval is 0.0238. There are 7 homozygotes in GnomAd4. There are 498 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012292.5. 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
	ARHGAP45	NM_012292.5	MANE Select	c.3096G>A	p.Ser1032Ser	synonymous	Exon 23 of 23	NP_036424.2
	ARHGAP45	NM_001258328.4		c.3144G>A	p.Ser1048Ser	synonymous	Exon 23 of 23	NP_001245257.1	Q92619-2
	ARHGAP45	NM_001321232.2		c.3108G>A	p.Ser1036Ser	synonymous	Exon 23 of 23	NP_001308161.1	K7ES98

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP45	ENST00000313093.7	TSL:1 MANE Select	c.3096G>A	p.Ser1032Ser	synonymous	Exon 23 of 23	ENSP00000316772.2	Q92619-1
	ARHGAP45	ENST00000586866.5	TSL:1	c.3108G>A	p.Ser1036Ser	synonymous	Exon 23 of 23	ENSP00000468615.1	K7ES98
	ARHGAP45	ENST00000885660.1		c.3180G>A	p.Ser1060Ser	synonymous	Exon 22 of 22	ENSP00000555719.1

Frequencies

GnomAD3 genomes AF: 0.00722 AC: 1085 AN: 150190 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00194

Gnomad ASJ AF: 0.00174

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00532

GnomAD2 exomes AF: 0.00182 AC: 425 AN: 234088 AF XY: 0.00150

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.00108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000352

GnomAD4 exome AF: 0.000781 AC: 1125 AN: 1440438 Hom.: 12 Cov.: 31 AF XY: 0.000680 AC XY: 485 AN XY: 713516

African (AFR) AF: 0.0254 AC: 837 AN: 32934

American (AMR) AF: 0.00122 AC: 52 AN: 42784

Ashkenazi Jewish (ASJ) AF: 0.00106 AC: 27 AN: 25466

East Asian (EAS) AF: 0.00 AC: 0 AN: 39180

South Asian (SAS) AF: 0.000129 AC: 11 AN: 84958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51884

Middle Eastern (MID) AF: 0.00281 AC: 16 AN: 5690

European-Non Finnish (NFE) AF: 0.0000692 AC: 76 AN: 1098214

Other (OTH) AF: 0.00179 AC: 106 AN: 59328

GnomAD4 genome AF: 0.00722 AC: 1086 AN: 150314 Hom.: 7 Cov.: 31 AF XY: 0.00679 AC XY: 498 AN XY: 73356

African (AFR) AF: 0.0251 AC: 1029 AN: 41002

American (AMR) AF: 0.00193 AC: 29 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 6 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67376

Other (OTH) AF: 0.00526 AC: 11 AN: 2090

Alfa AF: 0.00311 Hom.: 1

Bravo AF: 0.00837

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.0060
DANN	Benign	0.89
PhyloP100		-3.8
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs149960692; hg19: chr19-1085690; COSMIC: COSV99297546; COSMIC: COSV99297546;