3-131468049-CAAAAAA-CAA

Variant names:

• chr3-131468049-CAAAA-C
• rs56928817
• NM_007208.4:c.894+38_894+41delTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007208.4(MRPL3):​c.894+38_894+41delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000813 in 860,774 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000073 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: MRPL3 NM_007208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 0 publications found

Genes affected

MRPL3 (HGNC:10379): (mitochondrial ribosomal protein L3) 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 that belongs to the L3P ribosomal protein family. A pseudogene corresponding to this gene is found on chromosome 13q. [provided by RefSeq, Jul 2008]

MRPL3 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 9

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007208.4. 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
	MRPL3	NM_007208.4	MANE Select	c.894+38_894+41delTTTT		intron	N/A	NP_009139.1	P09001

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL3	ENST00000264995.8	TSL:1 MANE Select	c.894+38_894+41delTTTT		intron	N/A	ENSP00000264995.2	P09001
	MRPL3	ENST00000425847.6	TSL:2	c.975+38_975+41delTTTT		intron	N/A	ENSP00000398536.2	E7ETU7
	MRPL3	ENST00000511168.5	TSL:2	c.936+38_936+41delTTTT		intron	N/A	ENSP00000424107.1	H0Y9G6

Frequencies

GnomAD3 genomes AF: 0.00000726 AC: 1 AN: 137782 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000161

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000830 AC: 6 AN: 722992 Hom.: 0 AF XY: 0.0000134 AC XY: 5 AN XY: 372202

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12808

American (AMR) AF: 0.00 AC: 0 AN: 17968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14890

East Asian (EAS) AF: 0.00 AC: 0 AN: 27104

South Asian (SAS) AF: 0.0000253 AC: 1 AN: 39486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3032

European-Non Finnish (NFE) AF: 0.00000933 AC: 5 AN: 535960

Other (OTH) AF: 0.00 AC: 0 AN: 31558

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000726 AC: 1 AN: 137782 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66654

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 38942

American (AMR) AF: 0.00 AC: 0 AN: 13678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3112

East Asian (EAS) AF: 0.00 AC: 0 AN: 4550

South Asian (SAS) AF: 0.00 AC: 0 AN: 4186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.0000161 AC: 1 AN: 62220

Other (OTH) AF: 0.00 AC: 0 AN: 1906

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

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: rs56928817; hg19: chr3-131186893;