19-44893972-G-T

Variant names:

• chr19-44893972-G-T
• rs1160983
• NM_001128917.2:c.549G>T

Variant summary

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

The NM_001128917.2(TOMM40):​c.549G>T​(p.Ser183Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,407,680 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TOMM40 NM_001128917.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.39
• Publications: 0 publications found

Genes affected

TOMM40 (HGNC:18001): (translocase of outer mitochondrial membrane 40) The protein encoded by this gene is localized in the outer membrane of the mitochondria. It is the channel-forming subunit of the translocase of the mitochondrial outer membrane (TOM) complex that is essential for import of protein precursors into mitochondria. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2015]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128917.2. 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
	TOMM40	NM_001128917.2	MANE Select	c.549G>T	p.Ser183Ser	synonymous	Exon 5 of 9	NP_001122389.1	O96008-1
	TOMM40	NM_001128916.2		c.549G>T	p.Ser183Ser	synonymous	Exon 6 of 10	NP_001122388.1	O96008-1
	TOMM40	NM_006114.3		c.549G>T	p.Ser183Ser	synonymous	Exon 6 of 10	NP_006105.1	O96008-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMM40	ENST00000426677.7	TSL:1 MANE Select	c.549G>T	p.Ser183Ser	synonymous	Exon 5 of 9	ENSP00000410339.1	O96008-1
	TOMM40	ENST00000252487.9	TSL:1	c.549G>T	p.Ser183Ser	synonymous	Exon 6 of 10	ENSP00000252487.4	O96008-1
	TOMM40	ENST00000405636.6	TSL:1	c.549G>T	p.Ser183Ser	synonymous	Exon 6 of 10	ENSP00000385184.2	O96008-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1407680 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 694190

⚠️ 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: 32012

American (AMR) AF: 0.0000259 AC: 1 AN: 38658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22876

East Asian (EAS) AF: 0.00 AC: 0 AN: 38662

South Asian (SAS) AF: 0.00 AC: 0 AN: 78700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4602

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082348

Other (OTH) AF: 0.00 AC: 0 AN: 58060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	10
DANN	Benign	0.85
PhyloP100		-6.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 19

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

Other links and lift over

dbSNP: rs1160983; hg19: chr19-45397229;