3-109061989-T-A

Position:

• chr3-109061989-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_014429.4(MORC1):​c.965A>T​(p.Lys322Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,613,572 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0063 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (27 hom.)
• Consequence: MORC1 NM_014429.4 missense, splice_region
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.05

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 3-109061989-T-A is Benign according to our data. Variant chr3-109061989-T-A is described in ClinVar as [Benign]. Clinvar id is 713299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MORC1	NM_014429.4	c.965A>T	p.Lys322Met	missense_variant, splice_region_variant	11/28	ENST00000232603.10	NP_055244.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MORC1	ENST00000232603.10	c.965A>T	p.Lys322Met	missense_variant, splice_region_variant	11/28	1	NM_014429.4	ENSP00000232603	P2
MORC1	ENST00000483760.1	c.965A>T	p.Lys322Met	missense_variant, splice_region_variant	11/27	2		ENSP00000417282	A2

Frequencies

GnomAD3 genomes AF: 0.00631 AC: 960 AN: 152240 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00456

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00436 AC: 1096 AN: 251252 Hom.: 6 AF XY: 0.00412 AC XY: 560 AN XY: 135792

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.00444

Gnomad NFE exome AF: 0.00543

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00473 AC: 6911 AN: 1461214 Hom.: 27 Cov.: 31 AF XY: 0.00455 AC XY: 3309 AN XY: 726972

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.00489

Gnomad4 NFE exome AF: 0.00504

Gnomad4 OTH exome AF: 0.00454

GnomAD4 genome AF: 0.00632 AC: 963 AN: 152358 Hom.: 5 Cov.: 32 AF XY: 0.00628 AC XY: 468 AN XY: 74500

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00481

Gnomad4 NFE AF: 0.00456

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00460 Hom.: 0

Bravo AF: 0.00658

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00480 AC: 583

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00492

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.0068
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0076	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.80	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		0.061	B;.
Vest4		0.38
MVP		0.30
MPC		0.45
ClinPred		0.023	T
GERP RS		5.4
Varity_R		0.15
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.19		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: rs17225637; hg19: chr3-108780836; COSMIC: COSV105083065;