Genetic Variant UTF1:p.Ala65Val (chr10-133230482-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_003577.3(UTF1):c.194C>T(p.Ala65Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000068 in 1,441,218 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. A65S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 1 hom. )

Consequence

UTF1
NM_003577.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0520

Publications

0 publications found

Variant links:

Genes affected

UTF1 (HGNC:12634): (undifferentiated embryonic cell transcription factor 1) The protein encoded by this gene is a leucine zipper-containing transcriptional coactivator that may link the upstream activator ATF2 with the basal transcription complex. The encoded protein is closely associated with chromatin and is required for the proper differentiation of embryonic carcinoma and embryonic stem cells. Found nearly exclusively in pluripotent cells, this protein can also serve as a transcriptional repressor. [provided by RefSeq, Nov 2015]

UTF1 links:

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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=0.004241675).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003577.3. 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
	UTF1	NM_003577.3	MANE Select	c.194C>T	p.Ala65Val	missense	Exon 1 of 2	NP_003568.2	Q5T230

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UTF1	ENST00000304477.3	TSL:1 MANE Select	c.194C>T	p.Ala65Val	missense	Exon 1 of 2	ENSP00000305906.2	Q5T230

Frequencies

GnomAD3 genomes

AF:

0.0000793

AC:

AN:

151260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000443

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000337

AC:

AN:

71170

AF XY:

0.000388

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00330

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000387

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000667

AC:

AN:

1289852

Hom.:

Cov.:

AF XY:

0.0000707

AC XY:

AN XY:

636292

show subpopulations

African (AFR)

AF:

0.0000385

AC:

AN:

25942

American (AMR)

AF:

0.00

AC:

AN:

24026

Ashkenazi Jewish (ASJ)

AF:

0.00208

AC:

AN:

22074

East Asian (EAS)

AF:

0.00

AC:

AN:

26576

South Asian (SAS)

AF:

0.0000283

AC:

AN:

70654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32148

Middle Eastern (MID)

AF:

0.000266

AC:

AN:

3760

European-Non Finnish (NFE)

AF:

0.0000281

AC:

AN:

1031986

Other (OTH)

AF:

0.000133

AC:

AN:

52686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.0000793

AC:

AN:

151366

Hom.:

Cov.:

AF XY:

0.0000676

AC XY:

AN XY:

73982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15194

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

67760

Other (OTH)

AF:

0.00

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.0000712

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000277

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

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.51

M_CAP

Benign

0.039

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-0.052

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.98

REVEL

Benign

0.016

Sift

Benign

0.036

Sift4G

Benign

0.35

Polyphen

0.17

Vest4

0.14

MutPred

0.13

Gain of relative solvent accessibility (P = 0.09)

MVP

0.030

MPC

0.92

ClinPred

0.026

GERP RS

-0.49

PromoterAI

0.028

Neutral

(source)

Varity_R

0.12

gMVP

0.015

Mutation Taster

=93/7

polymorphism

(source)

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

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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