NM_004891.4:c.41+222A>C

Variant names:

• chr2-27772914-A-C
• rs3736594
• NM_004891.4:c.41+222A>C

Variant summary

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

The NM_004891.4(MRPL33):​c.41+222A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.674 in 505,392 control chromosomes in the GnomAD database, including 118,462 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 (30844 hom., cov: 32)
  • Exomes 𝑓: 0.70 (87618 hom.)
• Consequence: MRPL33 NM_004891.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300
• Publications: 38 publications found

Genes affected

MRPL33 (HGNC:14487): (mitochondrial ribosomal protein L33) 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. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004891.4. 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
	MRPL33	NM_004891.4	MANE Select	c.41+222A>C		intron	N/A	NP_004882.1	O75394-1
	MRPL33	NM_145330.3		c.41+222A>C		intron	N/A	NP_663303.1	O75394-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL33	ENST00000296102.8	TSL:1 MANE Select	c.41+222A>C		intron	N/A	ENSP00000296102.3	O75394-1
	MRPL33	ENST00000379666.7	TSL:1	c.41+222A>C		intron	N/A	ENSP00000368988.3	O75394-2
	MRPL33	ENST00000883033.1		c.22+1115A>C		intron	N/A	ENSP00000553092.1

Frequencies

GnomAD3 genomes AF: 0.621 AC: 94428 AN: 151950 Hom.: 30851 Cov.: 32

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.741

Gnomad OTH AF: 0.654

GnomAD4 exome AF: 0.697 AC: 246301 AN: 353324 Hom.: 87618 AF XY: 0.699 AC XY: 130817 AN XY: 187178

African (AFR) AF: 0.434 AC: 3851 AN: 8870

American (AMR) AF: 0.519 AC: 5353 AN: 10310

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 8187 AN: 11174

East Asian (EAS) AF: 0.472 AC: 11363 AN: 24078

South Asian (SAS) AF: 0.694 AC: 22387 AN: 32270

European-Finnish (FIN) AF: 0.682 AC: 16875 AN: 24754

Middle Eastern (MID) AF: 0.758 AC: 1229 AN: 1622

European-Non Finnish (NFE) AF: 0.742 AC: 162845 AN: 219398

Other (OTH) AF: 0.682 AC: 14211 AN: 20848

GnomAD4 genome AF: 0.621 AC: 94434 AN: 152068 Hom.: 30844 Cov.: 32 AF XY: 0.616 AC XY: 45777 AN XY: 74340

African (AFR) AF: 0.441 AC: 18261 AN: 41444

American (AMR) AF: 0.558 AC: 8525 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2561 AN: 3472

East Asian (EAS) AF: 0.416 AC: 2156 AN: 5184

South Asian (SAS) AF: 0.674 AC: 3249 AN: 4824

European-Finnish (FIN) AF: 0.681 AC: 7197 AN: 10568

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.741 AC: 50342 AN: 67976

Other (OTH) AF: 0.656 AC: 1384 AN: 2110

Alfa AF: 0.691 Hom.: 99699

Bravo AF: 0.598

Asia WGS AF: 0.519 AC: 1807 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.73
PhyloP100		-0.030
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: rs3736594; hg19: chr2-27995781;