3-131468049-CAAAAAA-CAAAA

Variant names:

• chr3-131468049-CAA-C
• rs56928817
• NM_007208.4:c.894+40_894+41delTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_007208.4(MRPL3):​c.894+40_894+41delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 833,282 control chromosomes in the GnomAD database, including 6 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 0)
  • Exomes 𝑓: 0.026 (6 hom.)
• Consequence: MRPL3 NM_007208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.292
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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+40_894+41delTT		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+40_894+41delTT		intron	N/A	ENSP00000264995.2	P09001
	MRPL3	ENST00000425847.6	TSL:2	c.975+40_975+41delTT		intron	N/A	ENSP00000398536.2	E7ETU7
	MRPL3	ENST00000511168.5	TSL:2	c.936+40_936+41delTT		intron	N/A	ENSP00000424107.1	H0Y9G6

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 160 AN: 137718 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00278

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.000220

Gnomad SAS AF: 0.00382

Gnomad FIN AF: 0.00211

Gnomad MID AF: 0.0110

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00105

GnomAD2 exomes AF: 0.0327 AC: 3677 AN: 112418 AF XY: 0.0343

Gnomad AFR exome AF: 0.0659

Gnomad AMR exome AF: 0.0267

Gnomad ASJ exome AF: 0.0501

Gnomad EAS exome AF: 0.0164

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.0336

Gnomad OTH exome AF: 0.0412

GnomAD4 exome AF: 0.0260 AC: 18072 AN: 695526 Hom.: 6 AF XY: 0.0269 AC XY: 9631 AN XY: 357476

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

African (AFR) AF: 0.0652 AC: 739 AN: 11338

American (AMR) AF: 0.0268 AC: 454 AN: 16966

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 501 AN: 14256

East Asian (EAS) AF: 0.0135 AC: 351 AN: 26008

South Asian (SAS) AF: 0.0355 AC: 1356 AN: 38206

European-Finnish (FIN) AF: 0.0178 AC: 678 AN: 38096

Middle Eastern (MID) AF: 0.0284 AC: 83 AN: 2924

European-Non Finnish (NFE) AF: 0.0251 AC: 13013 AN: 517484

Other (OTH) AF: 0.0297 AC: 897 AN: 30248

⚠️ 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: 0.00116 AC: 160 AN: 137756 Hom.: 0 Cov.: 0 AF XY: 0.00133 AC XY: 89 AN XY: 66680

African (AFR) AF: 0.000436 AC: 17 AN: 39010

American (AMR) AF: 0.00278 AC: 38 AN: 13686

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 34 AN: 3112

East Asian (EAS) AF: 0.000221 AC: 1 AN: 4534

South Asian (SAS) AF: 0.00384 AC: 16 AN: 4162

European-Finnish (FIN) AF: 0.00211 AC: 17 AN: 8052

Middle Eastern (MID) AF: 0.00800 AC: 2 AN: 250

European-Non Finnish (NFE) AF: 0.000515 AC: 32 AN: 62184

Other (OTH) AF: 0.00156 AC: 3 AN: 1918

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism

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;