3-49030576-C-T

Position:

• chr3-49030576-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_198880.3(QRICH1):​c.2207G>A​(p.Ser736Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: QRICH1 NM_198880.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.48

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]

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.
• PP5: Variant 3-49030576-C-T is Pathogenic according to our data. Variant chr3-49030576-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 929834.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-49030576-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
QRICH1	NM_198880.3	c.2207G>A	p.Ser736Asn	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.2207G>A	p.Ser736Asn	missense_variant	10/10	1	NM_198880.3	ENSP00000378830	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Ververi-Brady syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, University of Leipzig Medical Center	Dec 21, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, University Hospital of Duesseldorf	Jun 03, 2020	The QRICH1 NM_017730.3:c.2207G>A; p.(Ser736Asn) variant was identified as a de novo mutation in a child displaying the clinical features of Ververi Brady syndrome (PMID: 28692176). The child is the first child of healthy non-consanguineous parents. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 02, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	.;.;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.1	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.024	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.79
MutPred		0.36		Loss of glycosylation at S736 (P = 0.0184);Loss of glycosylation at S736 (P = 0.0184);Loss of glycosylation at S736 (P = 0.0184);
MVP		0.41
MPC		1.8
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.53
gMVP		0.77

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: rs2093229974; hg19: chr3-49068009;