21-36369052-C-G

Position:

• chr21-36369052-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015358.3(MORC3):​c.1684C>G​(p.Gln562Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MORC3 NM_015358.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

Genes affected

MORC3 (HGNC:23572): (MORC family CW-type zinc finger 3) This gene encodes a protein that localizes to the nuclear matrix and forms nuclear bodies via an ATP-dependent mechanism. The protein is predicted to have coiled-coil and zinc finger domains and has RNA binding activity. Alternative splicing produces multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.101622015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MORC3	NM_015358.3	c.1684C>G	p.Gln562Glu	missense_variant	15/17	ENST00000400485.6	NP_056173.1
MORC3	NM_001320445.2	c.1471C>G	p.Gln491Glu	missense_variant	14/16		NP_001307374.1
MORC3	NM_001320446.2	c.1471C>G	p.Gln491Glu	missense_variant	16/18		NP_001307375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MORC3	ENST00000400485.6	c.1684C>G	p.Gln562Glu	missense_variant	15/17	1	NM_015358.3	ENSP00000383333.1
MORC3	ENST00000484028.1	n.625C>G		non_coding_transcript_exon_variant	3/3	3
MORC3	ENST00000487909.5	n.1645C>G		non_coding_transcript_exon_variant	14/16	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jan 18, 2023

The c.1684C>G (p.Q562E) alteration is located in exon 15 (coding exon 15) of the MORC3 gene. This alteration results from a C to G substitution at nucleotide position 1684, causing the glutamine (Q) at amino acid position 562 to be replaced by a glutamic acid (E). 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	0.068
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.58
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.00092	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.055
Sift	Benign	0.16	T
Sift4G	Benign	1.0	T
Polyphen		0.028	B
Vest4		0.20
MutPred		0.12		Loss of MoRF binding (P = 0.0473);
MVP		0.44
MPC		0.22
ClinPred		0.25	T
GERP RS		3.9
Varity_R		0.14
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr21-37741350; COSMIC: COSV68688301; COSMIC: COSV68688301;