21-36369221-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.1853C>G(p.Pro618Arg) 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. 14/21 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: 0.582

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=0.09339002).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MORC3	NM_015358.3	c.1853C>G	p.Pro618Arg	missense_variant	15/17	ENST00000400485.6
MORC3	NM_001320445.2	c.1640C>G	p.Pro547Arg	missense_variant	14/16
MORC3	NM_001320446.2	c.1640C>G	p.Pro547Arg	missense_variant	16/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MORC3	ENST00000400485.6	c.1853C>G	p.Pro618Arg	missense_variant	15/17	1	NM_015358.3	P1
MORC3	ENST00000487909.5	n.1814C>G		non_coding_transcript_exon_variant	14/16	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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 16, 2024

The c.1853C>G (p.P618R) 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 1853, causing the proline (P) at amino acid position 618 to be replaced by an arginine (R). 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	0.082
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.091
Sift	Uncertain	0.015	D
Sift4G	Benign	0.32	T
Polyphen		0.68	P
Vest4		0.19
MutPred		0.19		Gain of phosphorylation at S616 (P = 0.1446);
MVP		0.13
MPC		0.31
ClinPred		0.18	T
GERP RS		-0.065
Varity_R		0.094
gMVP		0.37

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: chr21-37741519;