15-34886632-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014691.3(AQR):c.2711G>A(p.Arg904Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,310 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: AQR NM_014691.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

AQR (HGNC:29513): (aquarius intron-binding spliceosomal factor) Enables 3'-5' RNA helicase activity and single-stranded RNA binding activity. Involved in mRNA splicing, via spliceosome. Located in nucleoplasm. Part of U2-type catalytic step 2 spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, AQR

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQR	NM_014691.3	c.2711G>A	p.Arg904Gln	missense_variant	25/35	ENST00000156471.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQR	ENST00000156471.10	c.2711G>A	p.Arg904Gln	missense_variant	25/35	1	NM_014691.3	P1
AQR	ENST00000543879.6	c.*796G>A		3_prime_UTR_variant, NMD_transcript_variant	25/34	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248850 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135024

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 SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461310 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.2711G>A (p.R904Q) alteration is located in exon 25 (coding exon 25) of the AQR gene. This alteration results from a G to A substitution at nucleotide position 2711, causing the arginine (R) at amino acid position 904 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.59
Sift	Benign	0.046	D
Sift4G	Benign	0.078	T
Polyphen		0.49	P
Vest4		0.64
MutPred		0.46		Loss of MoRF binding (P = 0.0156);
MVP		0.84
MPC		1.7
ClinPred		0.91	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1158075610; hg19: chr15-35178833; COSMIC: COSV50041236;