Genetic Variant NM_017853.3:c.268A>G (chr16-72089003-T-C) – 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_017853.3(TXNL4B):c.268A>G(p.Met90Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,609,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M90K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

TXNL4B
NM_017853.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.76

Publications

0 publications found

Variant links:

Genes affected

TXNL4B (HGNC:26041): (thioredoxin like 4B) Predicted to be involved in mRNA splicing, via spliceosome. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TXNL4B links:

ENSG00000310525 (HGNC:):

ENSG00000310525 links:

Genome browser will be placed here

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_017853.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TXNL4B	NM_017853.3	MANE Select	c.268A>G	p.Met90Val	missense	Exon 3 of 4	NP_060323.1	Q9NX01
TXNL4B	NM_001142317.2		c.268A>G	p.Met90Val	missense	Exon 3 of 4	NP_001135789.1	Q9NX01
TXNL4B	NM_001142318.2		c.268A>G	p.Met90Val	missense	Exon 3 of 4	NP_001135790.1	Q9NX01

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TXNL4B	ENST00000268483.8	TSL:1 MANE Select	c.268A>G	p.Met90Val	missense	Exon 3 of 4	ENSP00000268483.3	Q9NX01
ENSG00000310525	ENST00000562153.6	TSL:4	n.268A>G		non_coding_transcript_exon	Exon 3 of 6	ENSP00000454635.2	H3BN11
TXNL4B	ENST00000423037.5	TSL:4	c.268A>G	p.Met90Val	missense	Exon 3 of 4	ENSP00000408130.1	Q9NX01

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250292

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000584

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1457684

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

724612

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33402

American (AMR)

AF:

0.0000449

AC:

AN:

44502

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1109012

Other (OTH)

AF:

0.0000166

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.2

PhyloP100

7.8

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.36

Sift

Benign

0.051

Sift4G

Benign

0.064

Polyphen

0.10

Vest4

0.92

MutPred

0.53

Gain of catalytic residue at M90 (P = 0.0175)

MVP

0.088

MPC

0.0049

ClinPred

0.39

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.59

gMVP

0.67

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over