21-36359959-C-T

Variant summary

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

The NM_015358.3(MORC3):c.1213C>T(p.Arg405Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: MORC3 NM_015358.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88

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=0.13489327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MORC3	NM_015358.3	c.1213C>T	p.Arg405Cys	missense_variant	11/17	ENST00000400485.6
MORC3	NM_001320445.2	c.1000C>T	p.Arg334Cys	missense_variant	10/16
MORC3	NM_001320446.2	c.1000C>T	p.Arg334Cys	missense_variant	12/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MORC3	ENST00000400485.6	c.1213C>T	p.Arg405Cys	missense_variant	11/17	1	NM_015358.3	P1
MORC3	ENST00000485299.1	n.597C>T		non_coding_transcript_exon_variant	4/4	3
MORC3	ENST00000487909.5	n.1174C>T		non_coding_transcript_exon_variant	10/16	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249392 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

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

Dec 19, 2022

The c.1213C>T (p.R405C) alteration is located in exon 11 (coding exon 11) of the MORC3 gene. This alteration results from a C to T substitution at nucleotide position 1213, causing the arginine (R) at amino acid position 405 to be replaced by a cysteine (C). 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	0.22
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.0064
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.10
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.053	T
Polyphen		0.14	B
Vest4		0.33
MutPred		0.45		Gain of methylation at K404 (P = 0.0371);
MVP		0.37
MPC		2.1
ClinPred		0.88	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs758552820; hg19: chr21-37732257; COSMIC: COSV68203755; COSMIC: COSV68203755;