rs144972972

Variant names:

• chr6-151430154-T-C
• rs144972972
• NM_017909.4:c.713A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_Strong BS1_Supporting

The NM_017909.4(RMND1):​c.713A>G​(p.Asn238Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000358 in 1,602,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: RMND1 NM_017909.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 U:1
• Conservation: PhyloP100: 5.59
• Publications: 22 publications found

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]

RMND1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• combined oxidative phosphorylation defect type 11

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PP5: Variant 6-151430154-T-C is Pathogenic according to our data. Variant chr6-151430154-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 225255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000237 (36/152164) while in subpopulation NFE AF = 0.00047 (32/68030). AF 95% confidence interval is 0.000342. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017909.4. 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
	RMND1	NM_017909.4	MANE Select	c.713A>G	p.Asn238Ser	missense	Exon 5 of 12	NP_060379.2	Q9NWS8-1
	RMND1	NM_001271937.2		c.203A>G	p.Asn68Ser	missense	Exon 4 of 11	NP_001258866.1	A0A087WXU0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMND1	ENST00000444024.3	TSL:3 MANE Select	c.713A>G	p.Asn238Ser	missense	Exon 5 of 12	ENSP00000412708.2	Q9NWS8-1
	RMND1	ENST00000682641.1		c.713A>G	p.Asn238Ser	missense	Exon 5 of 12	ENSP00000506793.1	A0A804HHW6
	RMND1	ENST00000949374.1		c.713A>G	p.Asn238Ser	missense	Exon 5 of 12	ENSP00000619433.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000201 AC: 50 AN: 249272 AF XY: 0.000230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000880

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000389

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000370 AC: 537 AN: 1450126 Hom.: 0 Cov.: 26 AF XY: 0.000375 AC XY: 271 AN XY: 721914

African (AFR) AF: 0.000121 AC: 4 AN: 33146

American (AMR) AF: 0.0000905 AC: 4 AN: 44212

Ashkenazi Jewish (ASJ) AF: 0.000655 AC: 17 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.0000586 AC: 5 AN: 85280

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.000433 AC: 478 AN: 1103058

Other (OTH) AF: 0.000417 AC: 25 AN: 59938

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74338

African (AFR) AF: 0.0000241 AC: 1 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000435 Hom.: 0

Bravo AF: 0.000298

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000173 AC: 21

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	1	-	Combined oxidative phosphorylation defect type 11 (6)
5	-	-	not provided (5)
1	-	-	Inborn genetic diseases (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Mitochondrial oxidative phosphorylation disorder (1)
1	-	-	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.94
MVP		0.69
MPC		0.71
ClinPred		0.67	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.64
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs144972972; hg19: chr6-151751289;