chr15-34873832-T-C

Variant names:

• chr15-34873832-T-C
• rs762410262
• NM_014691.3:c.3593A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014691.3(AQR):​c.3593A>G​(p.Tyr1198Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,418,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1198F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AQR NM_014691.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014691.3. 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
	AQR	NM_014691.3	MANE Select	c.3593A>G	p.Tyr1198Cys	missense	Exon 30 of 35	NP_055506.1	O60306

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQR	ENST00000156471.10	TSL:1 MANE Select	c.3593A>G	p.Tyr1198Cys	missense	Exon 30 of 35	ENSP00000156471.5	O60306
	AQR	ENST00000875393.1		c.3557A>G	p.Tyr1186Cys	missense	Exon 29 of 34	ENSP00000545452.1
	AQR	ENST00000945427.1		c.3536A>G	p.Tyr1179Cys	missense	Exon 29 of 34	ENSP00000615486.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1418176 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 702984

African (AFR) AF: 0.00 AC: 0 AN: 31620

American (AMR) AF: 0.00 AC: 0 AN: 39284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24468

East Asian (EAS) AF: 0.00 AC: 0 AN: 38616

South Asian (SAS) AF: 0.00 AC: 0 AN: 77840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5550

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1090166

Other (OTH) AF: 0.00 AC: 0 AN: 58372

GnomAD4 genome Cov.: 32

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	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.80	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.95	P
Vest4		0.89
MutPred		0.47		Loss of disorder (P = 0.08)
MVP		0.96
MPC		2.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.91
Mutation Taster		=25/75	disease causing

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: rs762410262; hg19: chr15-35166033;