NM_001128917.2:c.145A>C

Variant names:

• chr19-44891560-A-C
• rs1408274456
• NM_001128917.2:c.145A>C

Variant summary

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

The NM_001128917.2(TOMM40):​c.145A>C​(p.Ser49Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000156 in 1,285,336 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S49G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: TOMM40 NM_001128917.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0430
• 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: 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 (MetaRNN=0.058099568).

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.145A>C	p.Ser49Arg	missense	Exon 1 of 9	NP_001122389.1	O96008-1
	TOMM40	NM_001128916.2		c.145A>C	p.Ser49Arg	missense	Exon 2 of 10	NP_001122388.1	O96008-1
	TOMM40	NM_006114.3		c.145A>C	p.Ser49Arg	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.145A>C	p.Ser49Arg	missense	Exon 1 of 9	ENSP00000410339.1	O96008-1
	TOMM40	ENST00000252487.9	TSL:1	c.145A>C	p.Ser49Arg	missense	Exon 2 of 10	ENSP00000252487.4	O96008-1
	TOMM40	ENST00000405636.6	TSL:1	c.145A>C	p.Ser49Arg	missense	Exon 2 of 10	ENSP00000385184.2	O96008-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1285336 Hom.: 0 Cov.: 30 AF XY: 0.00000158 AC XY: 1 AN XY: 631626

African (AFR) AF: 0.00 AC: 0 AN: 26212

American (AMR) AF: 0.00 AC: 0 AN: 24018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22252

East Asian (EAS) AF: 0.00 AC: 0 AN: 27812

South Asian (SAS) AF: 0.00 AC: 0 AN: 69358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3752

European-Non Finnish (NFE) AF: 0.00000195 AC: 2 AN: 1026720

Other (OTH) AF: 0.00 AC: 0 AN: 52558

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.54
DEOGEN2	Benign	0.079	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.043
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.028
Sift	Benign	0.49	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.067
MutPred		0.26		Loss of glycosylation at S49 (P = 0.006)
MVP		0.043
MPC		0.057
ClinPred		0.037	T
GERP RS		0.83
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
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: rs1408274456; hg19: chr19-45394817;