chr19-44891562-T-G

Position:

• chr19-44891562-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000426677.7(TOMM40):​c.147T>G​(p.Ser49Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,441,996 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (24 hom., cov: 33)
  • Exomes 𝑓: 0.015 (184 hom.)
• Consequence: TOMM40 ENST00000426677.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.00

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028074384).
• BP6: Variant 19-44891562-T-G is Benign according to our data. Variant chr19-44891562-T-G is described in ClinVar as [Benign]. Clinvar id is 774355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1814/152240) while in subpopulation NFE AF= 0.0178 (1209/67978). AF 95% confidence interval is 0.017. There are 24 homozygotes in gnomad4. There are 904 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1814 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOMM40	NM_001128917.2	c.147T>G	p.Ser49Arg	missense_variant	1/9	ENST00000426677.7	NP_001122389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMM40	ENST00000426677.7	c.147T>G	p.Ser49Arg	missense_variant	1/9	1	NM_001128917.2	ENSP00000410339	P1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1814 AN: 152122 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0314

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00984 AC: 696 AN: 70734 Hom.: 9 AF XY: 0.0102 AC XY: 422 AN XY: 41454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00372

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00264

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0151 AC: 19458 AN: 1289756 Hom.: 184 Cov.: 30 AF XY: 0.0148 AC XY: 9383 AN XY: 634026

Gnomad4 AFR exome AF: 0.00183

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00273

Gnomad4 FIN exome AF: 0.0276

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.0119 AC: 1814 AN: 152240 Hom.: 24 Cov.: 33 AF XY: 0.0121 AC XY: 904 AN XY: 74462

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0314

Gnomad4 NFE AF: 0.0178

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0110 Hom.: 7

Bravo AF: 0.00941

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.000405 AC: 1

ESP6500EA AF: 0.0119 AC: 65

ExAC AF: 0.00276 AC: 182

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.9
DANN	Benign	0.54
DEOGEN2	Benign	0.079	T;T;.;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.67	T;.;T;.;T
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.35	N;N;.;N;.
REVEL	Benign	0.0090
Sift	Benign	0.49	T;T;.;T;.
Sift4G	Benign	0.58	T;T;T;T;T
Polyphen		0.0	B;B;B;B;.
Vest4		0.067
MutPred		0.26		Loss of glycosylation at S49 (P = 0.006);Loss of glycosylation at S49 (P = 0.006);Loss of glycosylation at S49 (P = 0.006);Loss of glycosylation at S49 (P = 0.006);Loss of glycosylation at S49 (P = 0.006);
MVP		0.043
MPC		0.057
ClinPred		0.00086	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026

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: rs11556510; hg19: chr19-45394819; COSMIC: COSV104577912; COSMIC: COSV104577912;