Variant 3-109032811-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014429.4(MORC1):c.1474T>C(p.Trp492Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,434,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MORC1
NM_014429.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.47

Variant links:

Genes affected

MORC1 (HGNC:7198): (MORC family CW-type zinc finger 1) This gene encodes the human homolog of mouse morc and like the mouse protein it is testis-specific. Mouse studies support a testis-specific function since only male knockout mice are infertile; infertility is the only apparent defect. These studies further support a role for this protein early in spermatogenesis, possibly by affecting entry into apoptosis because testis from knockout mice show greatly increased numbers of apoptotic cells. [provided by RefSeq, Jan 2009]

MORC1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MORC1	NM_014429.4 linkuse as main transcript	c.1474T>C	p.Trp492Arg	missense_variant	16/28	ENST00000232603.10	NP_055244.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MORC1	ENST00000232603.10 linkuse as main transcript	c.1474T>C	p.Trp492Arg	missense_variant	16/28	1	NM_014429.4	ENSP00000232603	P2	Q86VD1-1
MORC1	ENST00000483760.1 linkuse as main transcript	c.1474T>C	p.Trp492Arg	missense_variant	16/27	2		ENSP00000417282	A2	Q86VD1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000824

AC:

AN:

242652

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

130922

show subpopulations

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:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000105

AC:

AN:

1434726

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

714554

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000137

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.1474T>C (p.W492R) alteration is located in exon 16 (coding exon 16) of the MORC1 gene. This alteration results from a T to C substitution at nucleotide position 1474, causing the tryptophan (W) at amino acid position 492 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.093

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Benign

-0.67

MutationAssessor

Pathogenic

4.0

H;H

MutationTaster

Benign

0.55

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-14

D;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

D;.

Vest4

0.86

MutPred

0.86

Gain of solvent accessibility (P = 0.006);Gain of solvent accessibility (P = 0.006);

MVP

0.84

MPC

0.97

ClinPred

0.99

GERP RS

4.7

Varity_R

0.93

gMVP

0.62

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

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