17-81704178-T-C

Variant names:

• chr17-81704178-T-C
• rs35815547
• NM_002949.4:c.75-66T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002949.4(MRPL12):​c.75-66T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0657 in 1,507,612 control chromosomes in the GnomAD database, including 4,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (412 hom., cov: 33)
  • Exomes 𝑓: 0.066 (3876 hom.)
• Consequence: MRPL12 NM_002949.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.97

Genes affected

MRPL12 (HGNC:10378): (mitochondrial ribosomal protein L12) 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 which forms homodimers. In prokaryotic ribosomes, two L7/L12 dimers and one L10 protein form the L8 protein complex. [provided by RefSeq, Jul 2008]

ENSG00000262660 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-81704178-T-C is Benign according to our data. Variant chr17-81704178-T-C is described in ClinVar as [Benign]. Clinvar id is 676743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL12	NM_002949.4	c.75-66T>C		intron_variant	Intron 1 of 4	ENST00000333676.8	NP_002940.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL12	ENST00000333676.8	c.75-66T>C		intron_variant	Intron 1 of 4	1	NM_002949.4	ENSP00000333837.3
ENSG00000262660	ENST00000571730.1	c.75-66T>C		intron_variant	Intron 1 of 14	2		ENSP00000461324.1

Frequencies

GnomAD3 genomes AF: 0.0674 AC: 10237 AN: 151972 Hom.: 412 Cov.: 33

Gnomad AFR AF: 0.0719

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0562

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.0822

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0578

Gnomad OTH AF: 0.0599

GnomAD4 exome AF: 0.0655 AC: 88792 AN: 1355522 Hom.: 3876 AF XY: 0.0655 AC XY: 43687 AN XY: 666694

Gnomad4 AFR exome AF: 0.0702

Gnomad4 AMR exome AF: 0.0460

Gnomad4 ASJ exome AF: 0.0282

Gnomad4 EAS exome AF: 0.262

Gnomad4 SAS exome AF: 0.0729

Gnomad4 FIN exome AF: 0.0484

Gnomad4 NFE exome AF: 0.0598

Gnomad4 OTH exome AF: 0.0661

GnomAD4 genome AF: 0.0674 AC: 10245 AN: 152090 Hom.: 412 Cov.: 33 AF XY: 0.0675 AC XY: 5015 AN XY: 74348

Gnomad4 AFR AF: 0.0721

Gnomad4 AMR AF: 0.0562

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.0821

Gnomad4 FIN AF: 0.0536

Gnomad4 NFE AF: 0.0578

Gnomad4 OTH AF: 0.0588

Alfa AF: 0.0595 Hom.: 260

Bravo AF: 0.0689

Asia WGS AF: 0.150 AC: 521 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.76

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

LitVar

Other links and lift over

dbSNP: rs35815547; hg19: chr17-79671208; COSMIC: COSV61268993; COSMIC: COSV61268993;