chr21-36337835-G-A

Variant names:

• chr21-36337835-G-A
• rs754415398
• NM_015358.3:c.349G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015358.3(MORC3):​c.349G>A​(p.Val117Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,614,042 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MORC3 NM_015358.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59
• Publications: 3 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24178174).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MORC3	NM_015358.3	MANE Select	c.349G>A	p.Val117Ile	missense	Exon 4 of 17	NP_056173.1	Q14149
	MORC3	NM_001320445.2		c.136G>A	p.Val46Ile	missense	Exon 3 of 16	NP_001307374.1	B4DHJ4
	MORC3	NM_001320446.2		c.136G>A	p.Val46Ile	missense	Exon 5 of 18	NP_001307375.1	B4DHJ4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MORC3	ENST00000400485.6	TSL:1 MANE Select	c.349G>A	p.Val117Ile	missense	Exon 4 of 17	ENSP00000383333.1	Q14149
	MORC3	ENST00000492336.5	TSL:1	n.425G>A		non_coding_transcript_exon	Exon 4 of 5
	MORC3	ENST00000487909.5	TSL:2	n.310G>A		non_coding_transcript_exon	Exon 3 of 16

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249542 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461880 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.000131 AC: 2 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.0028	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.077
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.7	L
PhyloP100		5.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.58	N
REVEL	Uncertain	0.47
Sift	Benign	0.078	T
Sift4G	Benign	0.12	T
Polyphen		0.19	B
Vest4		0.24
MutPred		0.45		Loss of catalytic residue at V117 (P = 0.0841)
MVP		0.85
MPC		1.3
ClinPred		0.17	T
GERP RS		4.2
Varity_R		0.10
gMVP		0.81
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs754415398; hg19: chr21-37710133; COSMIC: COSV68688335; COSMIC: COSV68688335;