Genetic Variant MORC3:p.Ile37Val (chr21-36333715-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_015358.3(MORC3):c.109A>G(p.Ile37Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,606,018 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 1 hom. )

Consequence

MORC3
NM_015358.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.21

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3929564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MORC3	NM_015358.3 link	c.109A>G	p.Ile37Val	missense_variant	Exon 2 of 17	ENST00000400485.6	NP_056173.1	Q14149Q4VBZ9
MORC3	NM_001320446.2 link	c.-105A>G		5_prime_UTR_variant	Exon 3 of 18		NP_001307375.1	B4DHJ4
MORC3	NM_001320445.2 link	c.-101-3159A>G		intron_variant	Intron 1 of 15		NP_001307374.1	B4DHJ4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MORC3	ENST00000400485.6 link	c.109A>G	p.Ile37Val	missense_variant	Exon 2 of 17	1	NM_015358.3	ENSP00000383333.1	Q14149
MORC3	ENST00000492336.5 link	n.185A>G		non_coding_transcript_exon_variant	Exon 2 of 5	1
MORC3	ENST00000485933.1 link	n.297A>G		non_coding_transcript_exon_variant	Exon 1 of 2	5
MORC3	ENST00000487909.5 link	n.74-3159A>G		intron_variant	Intron 1 of 15	2

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1454188

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

723932

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

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:

0.00

Gnomad4 OTH exome

AF:

0.0000997

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151830

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74112

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.109A>G (p.I37V) alteration is located in exon 2 (coding exon 2) of the MORC3 gene. This alteration results from a A to G substitution at nucleotide position 109, causing the isoleucine (I) at amino acid position 37 to be replaced by a valine (V). 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

0.17

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.80

M_CAP

Benign

0.050

MetaRNN

Benign

0.39

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

1.1

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.76

REVEL

Uncertain

0.49

Sift

Benign

0.24

Sift4G

Benign

0.18

Polyphen

0.21

Vest4

0.45

MutPred

0.22

Gain of disorder (P = 0.3439);

MVP

0.77

MPC

1.4

ClinPred

0.85

GERP RS

5.5

Varity_R

0.21

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over