rs142521318

Positions:

• chr6-151433176-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_017909.4(RMND1):​c.668C>T​(p.Pro223Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000627 in 1,611,320 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (1 hom.)
• Consequence: RMND1 NM_017909.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.67

Genes affected

RMND1 (HGNC:21176): (required for meiotic nuclear division 1 homolog) The protein encoded by this gene belongs to the evolutionary conserved sif2 family of proteins that share the DUF155 domain in common. This protein is thought to be localized in the mitochondria and involved in mitochondrial translation. Mutations in this gene are associated with combined oxidative phosphorylation deficiency-11. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040447623).
• BP6: Variant 6-151433176-G-A is Benign according to our data. Variant chr6-151433176-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377025.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RMND1	NM_017909.4	c.668C>T	p.Pro223Leu	missense_variant	4/12	ENST00000444024.3	NP_060379.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RMND1	ENST00000444024.3	c.668C>T	p.Pro223Leu	missense_variant	4/12	3	NM_017909.4	ENSP00000412708	P1

Frequencies

GnomAD3 genomes AF: 0.000625 AC: 95 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000603 AC: 151 AN: 250568 Hom.: 1 AF XY: 0.000620 AC XY: 84 AN XY: 135500

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.000960

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000627 AC: 915 AN: 1459272 Hom.: 1 Cov.: 29 AF XY: 0.000588 AC XY: 427 AN XY: 726136

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.000307

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.000731

Gnomad4 OTH exome AF: 0.000481

GnomAD4 genome AF: 0.000625 AC: 95 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.000687 AC XY: 51 AN XY: 74272

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.000912

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000784 Hom.: 0

Bravo AF: 0.000510

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000741 AC: 90

EpiCase AF: 0.00109

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 30, 2022	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	T;T;T
Eigen	Benign	-0.092
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.79	.;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.040	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.2	.;D;.
REVEL	Benign	0.13
Sift	Benign	0.046	.;D;.
Sift4G	Benign	0.080	.;T;D
Polyphen		0.011	B;B;.
Vest4		0.26, 0.24
MVP		0.52
MPC		0.22
ClinPred		0.058	T
GERP RS		4.3
Varity_R		0.24
gMVP		0.60

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: rs142521318; hg19: chr6-151754311;