12-121654331-T-C

Variant names:

• chr12-121654331-T-C
• rs1555325466
• NM_173855.5:c.406A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173855.5(MORN3):​c.406A>G​(p.Ile136Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MORN3 NM_173855.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.349

Genes affected

MORN3 (HGNC:29807): (MORN repeat containing 3) Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03206286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MORN3	NM_173855.5	c.406A>G	p.Ile136Val	missense_variant	Exon 3 of 6	ENST00000355329.7	NP_776254.3
MORN3	NM_001363685.2	c.406A>G	p.Ile136Val	missense_variant	Exon 4 of 7		NP_001350614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MORN3	ENST00000355329.7	c.406A>G	p.Ile136Val	missense_variant	Exon 3 of 6	1	NM_173855.5	ENSP00000347486.3
MORN3	ENST00000542364.1	n.406A>G		non_coding_transcript_exon_variant	Exon 4 of 6	1		ENSP00000445643.1
MORN3	ENST00000392462.6	n.406A>G		non_coding_transcript_exon_variant	Exon 3 of 5	3		ENSP00000376255.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450788 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 720320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000233

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: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.406A>G (p.I136V) alteration is located in exon 3 (coding exon 3) of the MORN3 gene. This alteration results from a A to G substitution at nucleotide position 406, causing the isoleucine (I) at amino acid position 136 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	0.079
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.17	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.014
Sift	Benign	0.67	T
Sift4G	Benign	0.69	T
Polyphen		0.0030	B
Vest4		0.075
MutPred		0.31		Gain of disorder (P = 0.1631);
MVP		0.12
MPC		0.14
ClinPred		0.12	T
GERP RS		2.5
Varity_R		0.025
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555325466; hg19: chr12-122092237;