rs748960699

Variant names:

• chr19-44894057-G-A
• rs748960699
• NM_001128917.2:c.634G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-44894057-G-A
• chr19-44894057-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001128917.2(TOMM40):​c.634G>A​(p.Val212Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000735 in 1,361,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000073 (0 hom.)
• Consequence: TOMM40 NM_001128917.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17783558).
• BS2: High AC in GnomAdExome4 at 10 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.634G>A	p.Val212Met	missense	Exon 5 of 9	NP_001122389.1	O96008-1
	TOMM40	NM_001128916.2		c.634G>A	p.Val212Met	missense	Exon 6 of 10	NP_001122388.1	O96008-1
	TOMM40	NM_006114.3		c.634G>A	p.Val212Met	missense	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.634G>A	p.Val212Met	missense	Exon 5 of 9	ENSP00000410339.1	O96008-1
	TOMM40	ENST00000252487.9	TSL:1	c.634G>A	p.Val212Met	missense	Exon 6 of 10	ENSP00000252487.4	O96008-1
	TOMM40	ENST00000405636.6	TSL:1	c.634G>A	p.Val212Met	missense	Exon 6 of 10	ENSP00000385184.2	O96008-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000114 AC: 2 AN: 174976 AF XY: 0.0000217

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: 0.00000735 AC: 10 AN: 1361352 Hom.: 0 Cov.: 31 AF XY: 0.0000120 AC XY: 8 AN XY: 666452

African (AFR) AF: 0.00 AC: 0 AN: 30144

American (AMR) AF: 0.00 AC: 0 AN: 30556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20112

East Asian (EAS) AF: 0.00 AC: 0 AN: 37740

South Asian (SAS) AF: 0.0000706 AC: 5 AN: 70804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4356

European-Non Finnish (NFE) AF: 0.00000377 AC: 4 AN: 1061760

Other (OTH) AF: 0.0000179 AC: 1 AN: 55884

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000255 AC: 3

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	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.066
Sift	Benign	0.11	T
Sift4G	Benign	0.11	T
Polyphen		0.28	B
Vest4		0.41
MutPred		0.24		Loss of sheet (P = 0.0817)
MVP		0.082
MPC		1.0
ClinPred		0.15	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
Mutation Taster		=83/17	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: rs748960699; hg19: chr19-45397314;