19-44891587-C-A

Variant names:

• chr19-44891587-C-A
• rs775394719
• NM_001128917.2:c.172C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001128917.2(TOMM40):​c.172C>A​(p.Pro58Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000762 in 1,313,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P58S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: TOMM40 NM_001128917.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.522
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06924501).

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.172C>A	p.Pro58Thr	missense	Exon 1 of 9	NP_001122389.1	O96008-1
	TOMM40	NM_001128916.2		c.172C>A	p.Pro58Thr	missense	Exon 2 of 10	NP_001122388.1	O96008-1
	TOMM40	NM_006114.3		c.172C>A	p.Pro58Thr	missense	Exon 2 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.172C>A	p.Pro58Thr	missense	Exon 1 of 9	ENSP00000410339.1	O96008-1
	TOMM40	ENST00000252487.9	TSL:1	c.172C>A	p.Pro58Thr	missense	Exon 2 of 10	ENSP00000252487.4	O96008-1
	TOMM40	ENST00000405636.6	TSL:1	c.172C>A	p.Pro58Thr	missense	Exon 2 of 10	ENSP00000385184.2	O96008-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 75924 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.62e-7 AC: 1 AN: 1313056 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 646576

African (AFR) AF: 0.00 AC: 0 AN: 26564

American (AMR) AF: 0.00 AC: 0 AN: 26998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22832

East Asian (EAS) AF: 0.00 AC: 0 AN: 28694

South Asian (SAS) AF: 0.00 AC: 0 AN: 73192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3846

European-Non Finnish (NFE) AF: 9.58e-7 AC: 1 AN: 1043630

Other (OTH) AF: 0.00 AC: 0 AN: 54080

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000142 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.52
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.028
Sift	Benign	0.12	T
Sift4G	Uncertain	0.014	D
Polyphen		0.030	B
Vest4		0.14
MutPred		0.23		Gain of phosphorylation at P58 (P = 0.0025)
MVP		0.068
MPC		0.22
ClinPred		0.13	T
GERP RS		0.78
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.085
Mutation Taster		=89/11	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: rs775394719; hg19: chr19-45394844;