chr19-39480284-A-G

Variant names:

• chr19-39480284-A-G
• rs1327985920
• ENST00000544017.5:c.-261A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000544017.5(TIMM50):​c.-261A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 286,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TIMM50 ENST00000544017.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 0 publications found

Genes affected

TIMM50 (HGNC:23656): (translocase of inner mitochondrial membrane 50) This gene encodes a subunit of the TIM23 inner mitochondrial membrane translocase complex. The encoded protein functions as the receptor subunit that recognizes the mitochondrial targeting signal, or presequence, on protein cargo that is destined for the mitochondrial inner membrane and matrix. This protein may also play a role in maintaining the membrane permeability barrier, and knockdown of this gene in human cells results in the release of cytochrome c and apoptosis. [provided by RefSeq, Jul 2016]

TIMM50 Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria type 9

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM50	ENST00000544017.5	c.-261A>G		upstream_gene_variant		1		ENSP00000445806.2
TIMM50	ENST00000601358.5	n.-570A>G		upstream_gene_variant		1		ENSP00000472476.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000349 AC: 1 AN: 286256 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 148994

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

African (AFR) AF: 0.00 AC: 0 AN: 6568

American (AMR) AF: 0.00 AC: 0 AN: 8602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9442

East Asian (EAS) AF: 0.00 AC: 0 AN: 17192

South Asian (SAS) AF: 0.00 AC: 0 AN: 26324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1356

European-Non Finnish (NFE) AF: 0.00000557 AC: 1 AN: 179628

Other (OTH) AF: 0.00 AC: 0 AN: 17568

⚠️ 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 Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.3
DANN	Benign	0.17
PhyloP100		-1.4
PromoterAI		0.013	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1327985920; hg19: chr19-39970924;