rs16882046

Variant names:

• chr6-89664564-A-G
• rs16882046
• NM_014611.3:c.14159T>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014611.3(MDN1):​c.14159T>C​(p.Ile4720Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,613,510 control chromosomes in the GnomAD database, including 1,834 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.034 (126 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1708 hom.)
• Consequence: MDN1 NM_014611.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 7.36

Genes affected

MDN1 (HGNC:18302): (midasin AAA ATPase 1) Predicted to enable ATP binding activity. Involved in ribosomal large subunit assembly. Located in cytosol; intermediate filament cytoskeleton; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

MDN1-AS1 (HGNC:40837): (MDN1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016413033).
• BP6: Variant 6-89664564-A-G is Benign according to our data. Variant chr6-89664564-A-G is described in ClinVar as [Benign]. Clinvar id is 403077.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDN1	NM_014611.3	c.14159T>C	p.Ile4720Thr	missense_variant	Exon 85 of 102	ENST00000369393.8	NP_055426.1
MDN1-AS1	NR_111915.1	n.106-10832A>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDN1	ENST00000369393.8	c.14159T>C	p.Ile4720Thr	missense_variant	Exon 85 of 102	1	NM_014611.3	ENSP00000358400.3

Frequencies

GnomAD3 genomes AF: 0.0343 AC: 5222 AN: 152170 Hom.: 129 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0490

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.0395

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0229

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0372

GnomAD3 exomes AF: 0.0490 AC: 12320 AN: 251180 Hom.: 473 AF XY: 0.0525 AC XY: 7124 AN XY: 135774

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.0598

Gnomad ASJ exome AF: 0.0314

Gnomad EAS exome AF: 0.0404

Gnomad SAS exome AF: 0.130

Gnomad FIN exome AF: 0.0277

Gnomad NFE exome AF: 0.0350

Gnomad OTH exome AF: 0.0497

GnomAD4 exome AF: 0.0394 AC: 57561 AN: 1461222 Hom.: 1708 Cov.: 30 AF XY: 0.0420 AC XY: 30499 AN XY: 726944

Gnomad4 AFR exome AF: 0.0251

Gnomad4 AMR exome AF: 0.0580

Gnomad4 ASJ exome AF: 0.0321

Gnomad4 EAS exome AF: 0.0290

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.0291

Gnomad4 NFE exome AF: 0.0331

Gnomad4 OTH exome AF: 0.0456

GnomAD4 genome AF: 0.0343 AC: 5226 AN: 152288 Hom.: 126 Cov.: 32 AF XY: 0.0365 AC XY: 2720 AN XY: 74454

Gnomad4 AFR AF: 0.0211

Gnomad4 AMR AF: 0.0489

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.0390

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.0229

Gnomad4 NFE AF: 0.0331

Gnomad4 OTH AF: 0.0406

Alfa AF: 0.0357 Hom.: 247

Bravo AF: 0.0349

TwinsUK AF: 0.0399 AC: 148

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.0222 AC: 98

ESP6500EA AF: 0.0347 AC: 298

ExAC AF: 0.0487 AC: 5915

Asia WGS AF: 0.102 AC: 354 AN: 3478

EpiCase AF: 0.0384

EpiControl AF: 0.0401

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

MDN1-related disorder Benign:1

Jul 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.72
DEOGEN2	Benign	0.0051	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T;.
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.11
Sift	Benign	0.34	T;.
Polyphen		0.015	B;B
Vest4		0.11
MPC		0.25
ClinPred		0.032	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.032
gMVP		0.061

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

Other links and lift over

dbSNP: rs16882046; hg19: chr6-90374283;