NM_014763.4:c.658-9C>A

Variant names:

• chr2-75655055-C-A
• rs775408727
• NM_014763.4:c.658-9C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_014763.4(MRPL19):​c.658-9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 22)
  • Exomes 𝑓: 0.046 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRPL19 NM_014763.4 intron
• Scores: Splicing: ADA: 0.0006152
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.574
• Publications: 0 publications found

Genes affected

MRPL19 (HGNC:14052): (mitochondrial ribosomal protein L19) 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. [provided by RefSeq, Jul 2008]

GCFC2 (HGNC:1317): (GC-rich sequence DNA-binding factor 2) The first mRNA transcript isolated for this gene was part of an artificial chimera derived from two distinct gene transcripts and a primer used in the cloning process (see Genbank accession M29204). A positively charged amino terminus present only in the chimera was determined to bind GC-rich DNA, thus mistakenly thought to identify a transcription factor gene. [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=-0.67).
• BP6: Variant 2-75655055-C-A is Benign according to our data. Variant chr2-75655055-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 726493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014763.4. 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
	MRPL19	NM_014763.4	MANE Select	c.658-9C>A		intron	N/A	NP_055578.2	P49406

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL19	ENST00000393909.7	TSL:1 MANE Select	c.658-9C>A		intron	N/A	ENSP00000377486.2	P49406
	MRPL19	ENST00000409374.5	TSL:5	c.658-9C>A		intron	N/A	ENSP00000387284.1	P49406
	MRPL19	ENST00000884931.1		c.658-9C>A		intron	N/A	ENSP00000554990.1

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 148 AN: 81104 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00206

Gnomad AMI AF: 0.00211

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00842

Gnomad SAS AF: 0.00586

Gnomad FIN AF: 0.00362

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000889

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0459 AC: 28684 AN: 624820 Hom.: 0 Cov.: 19 AF XY: 0.0440 AC XY: 13937 AN XY: 316728

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

African (AFR) AF: 0.0456 AC: 613 AN: 13454

American (AMR) AF: 0.0180 AC: 293 AN: 16310

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 385 AN: 13104

East Asian (EAS) AF: 0.0298 AC: 724 AN: 24288

South Asian (SAS) AF: 0.0158 AC: 513 AN: 32384

European-Finnish (FIN) AF: 0.0164 AC: 617 AN: 37510

Middle Eastern (MID) AF: 0.0439 AC: 88 AN: 2004

European-Non Finnish (NFE) AF: 0.0530 AC: 24306 AN: 458416

Other (OTH) AF: 0.0419 AC: 1145 AN: 27350

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00184 AC: 149 AN: 81148 Hom.: 0 Cov.: 22 AF XY: 0.00209 AC XY: 80 AN XY: 38306

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

African (AFR) AF: 0.00219 AC: 49 AN: 22404

American (AMR) AF: 0.00248 AC: 18 AN: 7270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2100

East Asian (EAS) AF: 0.00805 AC: 20 AN: 2486

South Asian (SAS) AF: 0.00588 AC: 14 AN: 2382

European-Finnish (FIN) AF: 0.00362 AC: 12 AN: 3314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 114

European-Non Finnish (NFE) AF: 0.000889 AC: 35 AN: 39392

Other (OTH) AF: 0.00 AC: 0 AN: 1212

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.68
PhyloP100		0.57
PromoterAI		0.0056	Neutral
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00062
dbscSNV1_RF	Benign	0.042
SpliceAI score (max)		0.14		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: rs775408727; hg19: chr2-75882181;