NM_015956.3:c.740-8G>C

Variant names:

• chr19-10259609-G-C
• rs375741179
• NM_015956.3:c.740-8G>C

Variant summary

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

The NM_015956.3(MRPL4):​c.740-8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (0 hom., cov: 0)
  • Exomes 𝑓: 0.088 (105 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRPL4 NM_015956.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001430
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.31
• Publications: 0 publications found

Genes affected

MRPL4 (HGNC:14276): (mitochondrial ribosomal protein L4) 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. Sequence analysis identified alternatively spliced variants that encode different protein isoforms. [provided by RefSeq, Jul 2008]

LIMASI (HGNC:56357): (lncRNA inflammatory and mucous response associated, antisense to ICAM1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-10259609-G-C is Benign according to our data. Variant chr19-10259609-G-C is described in ClinVar as Benign. ClinVar VariationId is 403107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015956.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL4	NM_015956.3	MANE Select	c.740-8G>C		splice_region intron	N/A	NP_057040.2
	MRPL4	NM_001411149.1		c.*103G>C		3_prime_UTR	Exon 9 of 9	NP_001398078.1
	MRPL4	NM_146388.2		c.*871G>C		3_prime_UTR	Exon 8 of 8	NP_666500.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL4	ENST00000253099.11	TSL:1 MANE Select	c.740-8G>C		splice_region intron	N/A	ENSP00000253099.5
	MRPL4	ENST00000393733.6	TSL:5	c.*103G>C		3_prime_UTR	Exon 9 of 9	ENSP00000377334.2
	MRPL4	ENST00000930030.1		c.914-8G>C		splice_region intron	N/A	ENSP00000600089.1

Frequencies

GnomAD3 genomes AF: 0.324 AC: 7493 AN: 23160 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.282

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.0938

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.313

GnomAD2 exomes AF: 0.314 AC: 21608 AN: 68894 AF XY: 0.309

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.326

Gnomad FIN exome AF: 0.345

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.373

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0875 AC: 33862 AN: 386818 Hom.: 105 Cov.: 34 AF XY: 0.0969 AC XY: 18183 AN XY: 187656

African (AFR) AF: 0.139 AC: 1316 AN: 9434

American (AMR) AF: 0.365 AC: 4387 AN: 12022

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 1181 AN: 4674

East Asian (EAS) AF: 0.170 AC: 1266 AN: 7458

South Asian (SAS) AF: 0.290 AC: 5839 AN: 20108

European-Finnish (FIN) AF: 0.280 AC: 2101 AN: 7506

Middle Eastern (MID) AF: 0.109 AC: 108 AN: 988

European-Non Finnish (NFE) AF: 0.0518 AC: 16098 AN: 310510

Other (OTH) AF: 0.111 AC: 1566 AN: 14118

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.323 AC: 7493 AN: 23176 Hom.: 0 Cov.: 0 AF XY: 0.290 AC XY: 3396 AN XY: 11728

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

African (AFR) AF: 0.295 AC: 1931 AN: 6538

American (AMR) AF: 0.156 AC: 527 AN: 3386

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 206 AN: 478

East Asian (EAS) AF: 0.281 AC: 113 AN: 402

South Asian (SAS) AF: 0.338 AC: 134 AN: 396

European-Finnish (FIN) AF: 0.179 AC: 335 AN: 1874

Middle Eastern (MID) AF: 0.0938 AC: 3 AN: 32

European-Non Finnish (NFE) AF: 0.426 AC: 4107 AN: 9652

Other (OTH) AF: 0.311 AC: 105 AN: 338

⚠️ 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: 0.00249 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.45
DANN	Benign	0.50
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0040

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs375741179; hg19: chr19-10370285;