Genetic Variant NM_015084.3:c.840C>T (chr5-72223848-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_015084.3(MRPS27):c.840C>T(p.Leu280Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,613,032 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 20 hom. )

Consequence

MRPS27
NM_015084.3 splice_region, synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.492

Publications

2 publications found

Variant links:

Genes affected

MRPS27 (HGNC:14512): (mitochondrial ribosomal protein S27) 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 28S subunit protein that may be a functional partner of the death associated protein 3 (DAP3). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2013]

MRPS27 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 5-72223848-G-A is Benign according to our data. Variant chr5-72223848-G-A is described in ClinVar as Benign. ClinVar VariationId is 791396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.492 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00276 (420/152218) while in subpopulation AMR AF = 0.0176 (269/15292). AF 95% confidence interval is 0.0159. There are 4 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015084.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MRPS27	NM_015084.3	MANE Select	c.840C>T	p.Leu280Leu	splice_region synonymous	Exon 10 of 11	NP_055899.2	Q92552-1
MRPS27	NM_001286748.2		c.882C>T	p.Leu294Leu	splice_region synonymous	Exon 11 of 12	NP_001273677.1	Q92552-2
MRPS27	NM_001286751.2		c.672C>T	p.Leu224Leu	splice_region synonymous	Exon 10 of 11	NP_001273680.1	G5EA06

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MRPS27	ENST00000261413.10	TSL:1 MANE Select	c.840C>T	p.Leu280Leu	splice_region synonymous	Exon 10 of 11	ENSP00000261413.5	Q92552-1
MRPS27	ENST00000522562.5	TSL:1	n.*268C>T		splice_region non_coding_transcript_exon	Exon 7 of 7	ENSP00000511937.1	A0A8Q3WKM3
MRPS27	ENST00000522562.5	TSL:1	n.*268C>T		3_prime_UTR	Exon 7 of 7	ENSP00000511937.1	A0A8Q3WKM3

Frequencies

GnomAD3 genomes

AF:

0.00274

AC:

417

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000846

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0174

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0162

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00390

AC:

975

AN:

250034

AF XY:

0.00340

show subpopulations

Gnomad AFR exome

AF:

0.000742

Gnomad AMR exome

AF:

0.0169

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0180

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00263

GnomAD4 exome

AF:

0.00120

AC:

1752

AN:

1460814

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

823

AN XY:

726606

show subpopulations

African (AFR)

AF:

0.000389

AC:

AN:

33444

American (AMR)

AF:

0.0179

AC:

799

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.0161

AC:

637

AN:

39658

South Asian (SAS)

AF:

0.000708

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000999

AC:

111

AN:

1111340

Other (OTH)

AF:

0.00171

AC:

103

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

186

279

372

465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00276

AC:

420

AN:

152218

Hom.:

Cov.:

AF XY:

0.00323

AC XY:

240

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.000843

AC:

AN:

41514

American (AMR)

AF:

0.0176

AC:

269

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0162

AC:

AN:

5176

South Asian (SAS)

AF:

0.00166

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68024

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00138

Hom.:

Bravo

AF:

0.00411

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.53

(source)

DANN

Benign

0.19

PhyloP100

-0.49

Mutation Taster

=99/1

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over