NM_005932.4:c.1977C>T

Variant names:

• chr13-23756612-G-A
• rs73158528
• NM_005932.4:c.1977C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005932.4(MIPEP):​c.1977C>T​(p.Ala659Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00741 in 1,612,656 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (64 hom.)
• Consequence: MIPEP NM_005932.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.327
• Publications: 3 publications found

Genes affected

MIPEP (HGNC:7104): (mitochondrial intermediate peptidase) The product of this gene performs the final step in processing a specific class of nuclear-encoded proteins targeted to the mitochondrial matrix or inner membrane. This protein is primarily involved in the maturation of oxidative phosphorylation (OXPHOS)-related proteins. This gene may contribute to the functional effects of frataxin deficiency and the clinical manifestations of Friedreich ataxia. [provided by RefSeq, Jul 2008]

MIPEP Gene-Disease associations (from GenCC):

• lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae), Orphanet
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.1).
• BP6: Variant 13-23756612-G-A is Benign according to our data. Variant chr13-23756612-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 770419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.327 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00777 (1183/152304) while in subpopulation AMR AF = 0.011 (168/15294). AF 95% confidence interval is 0.00963. There are 6 homozygotes in GnomAd4. There are 542 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005932.4. 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
	MIPEP	NM_005932.4	MANE Select	c.1977C>T	p.Ala659Ala	synonymous	Exon 18 of 19	NP_005923.3	Q99797

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIPEP	ENST00000382172.4	TSL:1 MANE Select	c.1977C>T	p.Ala659Ala	synonymous	Exon 18 of 19	ENSP00000371607.3	Q99797
	MIPEP	ENST00000906723.1		c.1938C>T	p.Ala646Ala	synonymous	Exon 18 of 19	ENSP00000576782.1
	MIPEP	ENST00000906727.1		c.1899C>T	p.Ala633Ala	synonymous	Exon 17 of 18	ENSP00000576786.1

Frequencies

GnomAD3 genomes AF: 0.00772 AC: 1175 AN: 152188 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00835

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00870

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00623 AC: 1558 AN: 250222 AF XY: 0.00653

Gnomad AFR exome AF: 0.00838

Gnomad AMR exome AF: 0.00844

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00798

Gnomad OTH exome AF: 0.00669

GnomAD4 exome AF: 0.00737 AC: 10762 AN: 1460352 Hom.: 64 Cov.: 30 AF XY: 0.00737 AC XY: 5354 AN XY: 726584

African (AFR) AF: 0.00804 AC: 269 AN: 33476

American (AMR) AF: 0.00780 AC: 349 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00505 AC: 132 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00318 AC: 274 AN: 86246

European-Finnish (FIN) AF: 0.00121 AC: 63 AN: 52084

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.00826 AC: 9187 AN: 1111842

Other (OTH) AF: 0.00755 AC: 456 AN: 60384

GnomAD4 genome AF: 0.00777 AC: 1183 AN: 152304 Hom.: 6 Cov.: 33 AF XY: 0.00728 AC XY: 542 AN XY: 74468

African (AFR) AF: 0.00847 AC: 352 AN: 41568

American (AMR) AF: 0.0110 AC: 168 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00374 AC: 18 AN: 4812

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00872 AC: 593 AN: 68032

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00794 Hom.: 6

Bravo AF: 0.00835

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.10
DANN	Benign	0.71
PhyloP100		-0.33
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs73158528; hg19: chr13-24330751; COSMIC: COSV101193307;