6-89650840-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_014611.3(MDN1):c.15923T>C(p.Val5308Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000719 in 1,613,712 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (1 hom.)
• Consequence: MDN1 NM_014611.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.33

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:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MDN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0030017793).
• BP6: Variant 6-89650840-A-G is Benign according to our data. Variant chr6-89650840-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3052651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDN1	NM_014611.3	c.15923T>C	p.Val5308Ala	missense_variant	96/102	ENST00000369393.8
MDN1-AS1	NR_111915.1	n.105+12204A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDN1	ENST00000369393.8	c.15923T>C	p.Val5308Ala	missense_variant	96/102	1	NM_014611.3	P1

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000999 AC: 251 AN: 251254 Hom.: 2 AF XY: 0.00121 AC XY: 164 AN XY: 135768

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000845

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.000735 AC: 1074 AN: 1461396 Hom.: 1 Cov.: 30 AF XY: 0.000770 AC XY: 560 AN XY: 727056

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00815

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000893

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.000561

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74494

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.000589

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00101 AC: 122

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

MDN1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

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	0.049
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	20
Dann	Benign	0.92
DEOGEN2	Benign	0.0020	T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.55	T;.
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.2	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.85	N;.
REVEL	Benign	0.037
Sift	Benign	0.99	T;.
Polyphen		0.0	B;B
Vest4		0.057
MVP		0.068
MPC		0.18
ClinPred		0.013	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.014
gMVP		0.13

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: rs140535277; hg19: chr6-90360559;