Genetic Variant TCAIM:p.Ile16Leu (chr3-44357757-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173826.4(TCAIM):c.46A>T(p.Ile16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. I16V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TCAIM
NM_173826.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.12

Publications

0 publications found

Variant links:

Genes affected

TCAIM (HGNC:25241): (T cell activation inhibitor, mitochondrial) Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

TCAIM links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173826.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCAIM	NM_173826.4	MANE Select	c.46A>T	p.Ile16Leu	missense	Exon 3 of 11	NP_776187.2	Q8N3R3-1
TCAIM	NM_001282913.2		c.46A>T	p.Ile16Leu	missense	Exon 3 of 11	NP_001269842.1	Q8N3R3-1
TCAIM	NM_001029839.3		c.46A>T	p.Ile16Leu	missense	Exon 3 of 4	NP_001025010.1	Q8N3R3-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCAIM	ENST00000342649.9	TSL:1 MANE Select	c.46A>T	p.Ile16Leu	missense	Exon 3 of 11	ENSP00000341539.4	Q8N3R3-1
TCAIM	ENST00000383746.7	TSL:1	c.46A>T	p.Ile16Leu	missense	Exon 3 of 4	ENSP00000373252.3	Q8N3R3-3
TCAIM	ENST00000396078.7	TSL:1	c.46A>T	p.Ile16Leu	missense	Exon 3 of 4	ENSP00000379388.3	Q8N3R3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251320

AF XY:

0.00000736

show subpopulations

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:

6.84e-7

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727194

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.49

CADD

Benign

9.6

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.025

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.58

M_CAP

Benign

0.0073

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

1.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.27

REVEL

Benign

0.026

Sift

Benign

0.15

Sift4G

Benign

0.54

Polyphen

0.0080

Vest4

0.22

MutPred

0.30

Loss of catalytic residue at P18 (P = 0.0306)

MVP

0.30

MPC

0.21

ClinPred

0.018

GERP RS

0.52

Varity_R

0.040

gMVP

0.27

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.25

Position offset: -16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over