3-49030574-G-T

Position:

• chr3-49030574-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_198880.3(QRICH1):​c.2209C>A​(p.Pro737Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: QRICH1 NM_198880.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.49

Genes affected

QRICH1 (HGNC:24713): (glutamine rich 1) Enables DNA binding activity. Involved in several processes, including PERK-mediated unfolded protein response; intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; and positive regulation of transcription, DNA-templated. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000290315 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), QRICH1. . Gene score misZ 3.7104 (greater than the threshold 3.09). Trascript score misZ 3.7807 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, schizophrenia, Ververi-Brady syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
QRICH1	NM_198880.3	c.2209C>A	p.Pro737Thr	missense_variant	10/10	ENST00000395443.7	NP_942581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
QRICH1	ENST00000395443.7	c.2209C>A	p.Pro737Thr	missense_variant	10/10	1	NM_198880.3	ENSP00000378830.2
ENSG00000290315	ENST00000703936.1	c.2138+1609C>A		intron_variant				ENSP00000515567.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

QRICH1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2024

The QRICH1 c.2209C>A variant is predicted to result in the amino acid substitution p.Pro737Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;.;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.9	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0080	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.84
MutPred		0.55		Gain of catalytic residue at P737 (P = 0.0284);Gain of catalytic residue at P737 (P = 0.0284);Gain of catalytic residue at P737 (P = 0.0284);
MVP		0.31
MPC		1.9
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.63

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-49068007;