rs564387680

Variant names:

• chr19-44891608-G-C
• rs564387680
• NM_001128917.2:c.193G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-44891608-G-C
• chr19-44891608-G-T
• chr19-44891608-G-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001128917.2(TOMM40):​c.193G>C​(p.Ala65Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000604 in 1,323,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A65S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000060 (0 hom.)
• Consequence: TOMM40 NM_001128917.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.226
• Publications: 5 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05162278).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

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.193G>C	p.Ala65Pro	missense	Exon 1 of 9	NP_001122389.1	O96008-1
	TOMM40	NM_001128916.2		c.193G>C	p.Ala65Pro	missense	Exon 2 of 10	NP_001122388.1	O96008-1
	TOMM40	NM_006114.3		c.193G>C	p.Ala65Pro	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.193G>C	p.Ala65Pro	missense	Exon 1 of 9	ENSP00000410339.1	O96008-1
	TOMM40	ENST00000252487.9	TSL:1	c.193G>C	p.Ala65Pro	missense	Exon 2 of 10	ENSP00000252487.4	O96008-1
	TOMM40	ENST00000405636.6	TSL:1	c.193G>C	p.Ala65Pro	missense	Exon 2 of 10	ENSP00000385184.2	O96008-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000365 AC: 3 AN: 82130 AF XY: 0.0000423

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: 0.0000341

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000604 AC: 8 AN: 1323434 Hom.: 0 Cov.: 31 AF XY: 0.0000107 AC XY: 7 AN XY: 652534

African (AFR) AF: 0.00 AC: 0 AN: 26866

American (AMR) AF: 0.00 AC: 0 AN: 28288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23258

East Asian (EAS) AF: 0.00 AC: 0 AN: 29054

South Asian (SAS) AF: 0.0000673 AC: 5 AN: 74330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3870

European-Non Finnish (NFE) AF: 9.53e-7 AC: 1 AN: 1049838

Other (OTH) AF: 0.0000366 AC: 2 AN: 54646

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000138 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.082	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.23
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.013
Sift	Benign	0.080	T
Sift4G	Benign	0.25	T
Polyphen		0.13	B
Vest4		0.078
MutPred		0.14		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.14
MPC		0.078
ClinPred		0.031	T
GERP RS		1.7
PromoterAI		-0.0047	Neutral
Varity_R		0.049
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs564387680; hg19: chr19-45394865;