1-151760903-CAAAAAAAAAAAA-CAAAAAAAAAA

Variant names:

• chr1-151760903-CAA-C
• rs755031728
• NM_031420.4:c.589-6_589-5delTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031420.4(MRPL9):​c.589-6_589-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0426 in 919,182 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 0)
  • Exomes 𝑓: 0.046 (0 hom.)
• Consequence: MRPL9 NM_031420.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.93
• Publications: 1 publications found

Genes affected

MRPL9 (HGNC:14277): (mitochondrial ribosomal protein L9) This is a nuclear gene encoding a protein component of the 39S subunit of the mitochondrial ribosome. Alternative splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 8. [provided by RefSeq, Jul 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0568) population. However there is too low homozygotes in high coverage region: (expected more than 416, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL9	NM_031420.4	c.589-6_589-5delTT		splice_region_variant, intron_variant	Intron 5 of 6	ENST00000368830.8	NP_113608.1
MRPL9	NM_001300733.2	c.487-6_487-5delTT		splice_region_variant, intron_variant	Intron 4 of 5		NP_001287662.1
MRPL9	NR_125331.2	n.646-6_646-5delTT		splice_region_variant, intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL9	ENST00000368830.8	c.589-6_589-5delTT		splice_region_variant, intron_variant	Intron 5 of 6	1	NM_031420.4	ENSP00000357823.3

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 20 AN: 74192 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000111

Gnomad AMI AF: 0.00183

Gnomad AMR AF: 0.000153

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00250

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000282

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0463 AC: 39101 AN: 844996 Hom.: 0 AF XY: 0.0466 AC XY: 19542 AN XY: 419144

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

African (AFR) AF: 0.0309 AC: 535 AN: 17304

American (AMR) AF: 0.0430 AC: 547 AN: 12710

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 478 AN: 12956

East Asian (EAS) AF: 0.0419 AC: 1151 AN: 27488

South Asian (SAS) AF: 0.0587 AC: 2415 AN: 41110

European-Finnish (FIN) AF: 0.0349 AC: 815 AN: 23340

Middle Eastern (MID) AF: 0.0474 AC: 122 AN: 2572

European-Non Finnish (NFE) AF: 0.0468 AC: 31380 AN: 671220

Other (OTH) AF: 0.0457 AC: 1658 AN: 36296

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000270 AC: 20 AN: 74186 Hom.: 0 Cov.: 0 AF XY: 0.000353 AC XY: 12 AN XY: 33956

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

African (AFR) AF: 0.000111 AC: 2 AN: 18076

American (AMR) AF: 0.000153 AC: 1 AN: 6542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2212

East Asian (EAS) AF: 0.00 AC: 0 AN: 2640

South Asian (SAS) AF: 0.00 AC: 0 AN: 2044

European-Finnish (FIN) AF: 0.00250 AC: 5 AN: 2000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 102

European-Non Finnish (NFE) AF: 0.000282 AC: 11 AN: 39030

Other (OTH) AF: 0.00 AC: 0 AN: 994

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 231

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs755031728; hg19: chr1-151733379;