Genetic Variant TFEC:p.Ala279Thr (chr7-115940760-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012252.4(TFEC):c.835G>A(p.Ala279Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. A279P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TFEC
NM_012252.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.520

Publications

1 publications found

Variant links:

Genes affected

TFEC (HGNC:11754): (transcription factor EC) This gene encodes a member of the micropthalmia (MiT) family of basic helix-loop-helix leucine zipper transcription factors. MiT transcription factors regulate the expression of target genes by binding to E-box recognition sequences as homo- or heterodimers, and play roles in multiple cellular processes including survival, growth and differentiation. The encoded protein is a transcriptional activator of the nonmuscle myosin II heavy chain-A gene, and may also co-regulate target genes in osteoclasts as a heterodimer with micropthalmia-associated transcription factor. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

TFEC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047526002).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012252.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFEC	NM_012252.4	MANE Select	c.835G>A	p.Ala279Thr	missense	Exon 8 of 8	NP_036384.1	O14948-1
TFEC	NM_001018058.3		c.748G>A	p.Ala250Thr	missense	Exon 7 of 7	NP_001018068.1	O14948-2
TFEC	NM_001244583.2		c.634G>A	p.Ala212Thr	missense	Exon 6 of 6	NP_001231512.1	O14948-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFEC	ENST00000265440.12	TSL:1 MANE Select	c.835G>A	p.Ala279Thr	missense	Exon 8 of 8	ENSP00000265440.7	O14948-1
TFEC	ENST00000320239.11	TSL:1	c.748G>A	p.Ala250Thr	missense	Exon 7 of 7	ENSP00000318676.7	O14948-2
TFEC	ENST00000871199.1		c.835G>A	p.Ala279Thr	missense	Exon 10 of 10	ENSP00000541258.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250996

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

1461358

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.0000224

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111652

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00000658

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.26

DEOGEN2

Benign

0.22

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.021

MetaRNN

Benign

0.048

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

PhyloP100

0.52

PrimateAI

Benign

0.41

PROVEAN

Benign

0.79

REVEL

Benign

0.038

Sift

Benign

1.0

Sift4G

Benign

0.80

Polyphen

0.24

Vest4

0.028

MutPred

0.40

Loss of catalytic residue at A279 (P = 0.1128)

MVP

0.34

MPC

0.13

ClinPred

0.18

GERP RS

3.4

Varity_R

0.040

gMVP

0.094

Mutation Taster

=82/18

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