Genetic Variant NM_004891.4:c.41+222A>C (chr2-27772914-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0300

Publications

38 publications found

Variant links:

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]

MRPL33 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL33	NM_004891.4 link	c.41+222A>C		intron_variant	Intron 2 of 3	ENST00000296102.8	NP_004882.1	O75394-1
MRPL33	NM_145330.3 link	c.41+222A>C		intron_variant	Intron 2 of 2		NP_663303.1	O75394-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL33	ENST00000296102.8 link	c.41+222A>C		intron_variant	Intron 2 of 3	1	NM_004891.4	ENSP00000296102.3		O75394-1

Frequencies

GnomAD3 genomes

AF:

0.621

AC:

94428

AN:

151950

Hom.:

30851

Cov.:

show subpopulations

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

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

3318

6637

9955

13274

16592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

524

1048

1572

2096

2620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.621

AC:

94434

AN:

152068

Hom.:

30844

Cov.:

AF XY:

0.616

AC XY:

45777

AN XY:

74340

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1731

3462

5194

6925

8656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

776

1552

2328

3104

3880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

3.4

(source)

DANN

Benign

0.73

PhyloP100

-0.030

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over