19-44893972-G-A

Variant names:

• chr19-44893972-G-A
• rs1160983
• NM_001128917.2:c.549G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001128917.2(TOMM40):​c.549G>A​(p.Ser183Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0332 in 1,559,834 control chromosomes in the GnomAD database, including 1,117 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.048 (256 hom., cov: 32)
  • Exomes 𝑓: 0.032 (861 hom.)
• Consequence: TOMM40 NM_001128917.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.39
• Publications: 28 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP7: Synonymous conserved (PhyloP=-6.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0841 is higher than 0.05.

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.549G>A	p.Ser183Ser	synonymous	Exon 5 of 9	NP_001122389.1	O96008-1
	TOMM40	NM_001128916.2		c.549G>A	p.Ser183Ser	synonymous	Exon 6 of 10	NP_001122388.1	O96008-1
	TOMM40	NM_006114.3		c.549G>A	p.Ser183Ser	synonymous	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.549G>A	p.Ser183Ser	synonymous	Exon 5 of 9	ENSP00000410339.1	O96008-1
	TOMM40	ENST00000252487.9	TSL:1	c.549G>A	p.Ser183Ser	synonymous	Exon 6 of 10	ENSP00000252487.4	O96008-1
	TOMM40	ENST00000405636.6	TSL:1	c.549G>A	p.Ser183Ser	synonymous	Exon 6 of 10	ENSP00000385184.2	O96008-1

Frequencies

GnomAD3 genomes AF: 0.0476 AC: 7246 AN: 152140 Hom.: 256 Cov.: 32

Gnomad AFR AF: 0.0867

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0288

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.0765

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.0502

GnomAD2 exomes AF: 0.0354 AC: 7442 AN: 209954 AF XY: 0.0331

Gnomad AFR exome AF: 0.0889

Gnomad AMR exome AF: 0.0175

Gnomad ASJ exome AF: 0.0433

Gnomad EAS exome AF: 0.0736

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.0342

Gnomad OTH exome AF: 0.0331

GnomAD4 exome AF: 0.0316 AC: 44531 AN: 1407576 Hom.: 861 Cov.: 32 AF XY: 0.0309 AC XY: 21445 AN XY: 694134

African (AFR) AF: 0.0888 AC: 2843 AN: 32006

American (AMR) AF: 0.0181 AC: 700 AN: 38650

Ashkenazi Jewish (ASJ) AF: 0.0410 AC: 939 AN: 22876

East Asian (EAS) AF: 0.0628 AC: 2428 AN: 38658

South Asian (SAS) AF: 0.00774 AC: 609 AN: 78698

European-Finnish (FIN) AF: 0.0197 AC: 1020 AN: 51762

Middle Eastern (MID) AF: 0.0346 AC: 159 AN: 4602

European-Non Finnish (NFE) AF: 0.0314 AC: 33937 AN: 1082270

Other (OTH) AF: 0.0327 AC: 1896 AN: 58054

GnomAD4 genome AF: 0.0476 AC: 7250 AN: 152258 Hom.: 256 Cov.: 32 AF XY: 0.0467 AC XY: 3477 AN XY: 74446

African (AFR) AF: 0.0865 AC: 3592 AN: 41534

American (AMR) AF: 0.0288 AC: 440 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.0769 AC: 398 AN: 5176

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4830

European-Finnish (FIN) AF: 0.0150 AC: 159 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0347 AC: 2359 AN: 68024

Other (OTH) AF: 0.0516 AC: 109 AN: 2112

Alfa AF: 0.0436 Hom.: 57

Bravo AF: 0.0501

Asia WGS AF: 0.0570 AC: 199 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.4
DANN	Benign	0.87
PhyloP100		-6.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1160983; hg19: chr19-45397229; COSMIC: COSV52977056; COSMIC: COSV52977056;