Genetic Variant MORC3:p.Pro479Leu (chr21-36362212-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_015358.3(MORC3):c.1436C>T(p.Pro479Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,608,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MORC3
NM_015358.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.22

Publications

2 publications found

Variant links:

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]

MORC3 links:

ENSG00000228107 (HGNC:):

ENSG00000228107 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018215507).

BP6

Variant 21-36362212-C-T is Benign according to our data. Variant chr21-36362212-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3397462.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015358.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MORC3	NM_015358.3	MANE Select	c.1436C>T	p.Pro479Leu	missense	Exon 13 of 17	NP_056173.1	Q14149
MORC3	NM_001320445.2		c.1223C>T	p.Pro408Leu	missense	Exon 12 of 16	NP_001307374.1	B4DHJ4
MORC3	NM_001320446.2		c.1223C>T	p.Pro408Leu	missense	Exon 14 of 18	NP_001307375.1	B4DHJ4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MORC3	ENST00000400485.6	TSL:1 MANE Select	c.1436C>T	p.Pro479Leu	missense	Exon 13 of 17	ENSP00000383333.1	Q14149
MORC3	ENST00000484028.1	TSL:3	n.377C>T		non_coding_transcript_exon	Exon 1 of 3
MORC3	ENST00000487909.5	TSL:2	n.1397C>T		non_coding_transcript_exon	Exon 12 of 16

Frequencies

GnomAD3 genomes

AF:

0.0000400

AC:

AN:

150094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000978

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000421

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000285

AC:

AN:

245324

AF XY:

0.0000225

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000171

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000894

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1458338

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725586

show subpopulations

African (AFR)

AF:

0.0000905

AC:

AN:

33152

American (AMR)

AF:

0.00

AC:

AN:

43742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.000177

AC:

AN:

39654

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53064

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110992

Other (OTH)

AF:

0.00

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000400

AC:

AN:

150126

Hom.:

Cov.:

AF XY:

0.0000547

AC XY:

AN XY:

73078

show subpopulations

African (AFR)

AF:

0.0000977

AC:

AN:

40962

American (AMR)

AF:

0.00

AC:

AN:

15068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.000424

AC:

AN:

4722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67722

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000329

Hom.:

ExAC

AF:

0.0000497

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.73

CADD

Benign

9.7

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.073

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.71

M_CAP

Benign

0.0068

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

-1.2

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.38

REVEL

Benign

0.012

Sift

Benign

0.32

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.087

MVP

0.082

MPC

0.19

ClinPred

0.035

GERP RS

0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.039

gMVP

0.35

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over