19-44900743-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001128917.2(TOMM40):c.657C>T(p.Ala219=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00092 in 1,612,452 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (4 hom.)
• Consequence: TOMM40 NM_001128917.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.18

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 19-44900743-C-T is Benign according to our data. Variant chr19-44900743-C-T is described in ClinVar as [Benign]. Clinvar id is 783843.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000531 (776/1460136) while in subpopulation AFR AF= 0.0168 (563/33424). AF 95% confidence interval is 0.0157. There are 4 homozygotes in gnomad4_exome. There are 331 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 707 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOMM40	NM_001128917.2	c.657C>T	p.Ala219=	synonymous_variant	6/9	ENST00000426677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOMM40	ENST00000426677.7	c.657C>T	p.Ala219=	synonymous_variant	6/9	1	NM_001128917.2	P1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 707 AN: 152198 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00125 AC: 314 AN: 251258 Hom.: 2 AF XY: 0.000921 AC XY: 125 AN XY: 135792

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000531 AC: 776 AN: 1460136 Hom.: 4 Cov.: 33 AF XY: 0.000456 AC XY: 331 AN XY: 726408

Gnomad4 AFR exome AF: 0.0168

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00464 AC: 707 AN: 152316 Hom.: 7 Cov.: 33 AF XY: 0.00430 AC XY: 320 AN XY: 74474

Gnomad4 AFR AF: 0.0153

Gnomad4 AMR AF: 0.00398

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00132 Hom.: 2

Bravo AF: 0.00541

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 10, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	9.6
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs34459630; hg19: chr19-45404000;