chr21-25587877-T-G

Variant names:

• chr21-25587877-T-G
• rs2829806
• NM_017446.4:c.969+958A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_080794.4(MRPL39):​c.970-88A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.671 in 970,970 control chromosomes in the GnomAD database, including 231,300 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.62 (31273 hom., cov: 32)
  • Exomes 𝑓: 0.68 (200027 hom.)
• Consequence: MRPL39 NM_080794.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 21 publications found

Genes affected

MRPL39 (HGNC:14027): (mitochondrial ribosomal protein L39) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. Two transcript variants encoding distinct isoforms have been described. A pseudogene corresponding to this gene is found on chromosome 5q. [provided by RefSeq, Jul 2008]

MRPL39 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080794.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL39	NM_017446.4	MANE Select	c.969+958A>C		intron	N/A	NP_059142.3
	MRPL39	NM_080794.4		c.970-88A>C		intron	N/A	NP_542984.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL39	ENST00000352957.9	TSL:1 MANE Select	c.969+958A>C		intron	N/A	ENSP00000284967.7
	MRPL39	ENST00000307301.11	TSL:5	c.970-88A>C		intron	N/A	ENSP00000305682.7
	MRPL39	ENST00000925346.1		c.987+958A>C		intron	N/A	ENSP00000595405.1

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94592 AN: 151930 Hom.: 31272 Cov.: 32

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.681

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.701

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.751

Gnomad OTH AF: 0.666

GnomAD4 exome AF: 0.681 AC: 557361 AN: 818922 Hom.: 200027 AF XY: 0.675 AC XY: 288130 AN XY: 426982

African (AFR) AF: 0.468 AC: 9788 AN: 20932

American (AMR) AF: 0.458 AC: 16663 AN: 36366

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 17512 AN: 21276

East Asian (EAS) AF: 0.179 AC: 6324 AN: 35274

South Asian (SAS) AF: 0.465 AC: 31652 AN: 68032

European-Finnish (FIN) AF: 0.709 AC: 33057 AN: 46644

Middle Eastern (MID) AF: 0.729 AC: 3212 AN: 4408

European-Non Finnish (NFE) AF: 0.754 AC: 412308 AN: 546760

Other (OTH) AF: 0.684 AC: 26845 AN: 39230

GnomAD4 genome AF: 0.622 AC: 94619 AN: 152048 Hom.: 31273 Cov.: 32 AF XY: 0.613 AC XY: 45584 AN XY: 74358

African (AFR) AF: 0.469 AC: 19424 AN: 41432

American (AMR) AF: 0.560 AC: 8552 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2833 AN: 3468

East Asian (EAS) AF: 0.197 AC: 1016 AN: 5166

South Asian (SAS) AF: 0.437 AC: 2105 AN: 4820

European-Finnish (FIN) AF: 0.701 AC: 7411 AN: 10572

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.751 AC: 51057 AN: 67992

Other (OTH) AF: 0.660 AC: 1393 AN: 2112

Alfa AF: 0.707 Hom.: 19930

Bravo AF: 0.608

Asia WGS AF: 0.320 AC: 1118 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.13
DANN	Benign	0.55
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2829806; hg19: chr21-26960189; COSMIC: COSV56260810; COSMIC: COSV56260810;