Genetic Variant MTF1:p.Thr364Ile (chr1-37823790-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005955.3(MTF1):c.1091C>T(p.Thr364Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00482 in 1,613,962 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 27 hom. )

Consequence

MTF1
NM_005955.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.10

Publications

8 publications found

Variant links:

Genes affected

MTF1 (HGNC:7428): (metal regulatory transcription factor 1) This gene encodes a transcription factor that induces expression of metallothioneins and other genes involved in metal homeostasis in response to heavy metals such as cadmium, zinc, copper, and silver. The protein is a nucleocytoplasmic shuttling protein that accumulates in the nucleus upon heavy metal exposure and binds to promoters containing a metal-responsive element (MRE). [provided by RefSeq, Jul 2008]

MTF1 Gene-Disease associations (from GenCC):

intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: G2P

MTF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004799485).

BP6

Variant 1-37823790-G-A is Benign according to our data. Variant chr1-37823790-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 715469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 420 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTF1	NM_005955.3 link	c.1091C>T	p.Thr364Ile	missense_variant	Exon 8 of 11	ENST00000373036.5	NP_005946.2	Q14872

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTF1	ENST00000373036.5 link	c.1091C>T	p.Thr364Ile	missense_variant	Exon 8 of 11	1	NM_005955.3	ENSP00000362127.3		Q14872

Frequencies

GnomAD3 genomes

AF:

0.00276

AC:

420

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00498

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00251

AC:

630

AN:

251398

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000924

Gnomad NFE exome

AF:

0.00426

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00503

AC:

7356

AN:

1461666

Hom.:

Cov.:

AF XY:

0.00499

AC XY:

3626

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33478

American (AMR)

AF:

0.00125

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000842

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00116

AC:

100

AN:

86246

European-Finnish (FIN)

AF:

0.00110

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00609

AC:

6772

AN:

1111836

Other (OTH)

AF:

0.00517

AC:

312

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

363

726

1088

1451

1814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

268

536

804

1072

1340

<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:

0.00276

AC:

420

AN:

152296

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

195

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000938

AC:

AN:

41566

American (AMR)

AF:

0.00105

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00145

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00498

AC:

339

AN:

68020

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

104

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:

0.00416

Hom.:

Bravo

AF:

0.00284

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00247

AC:

300

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00562

EpiControl

AF:

0.00421

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.83

M_CAP

Benign

0.0094

MetaRNN

Benign

0.0048

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

4.1

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

REVEL

Benign

0.074

Sift

Benign

0.043

Sift4G

Benign

0.23

Polyphen

0.88

Vest4

0.51

MVP

0.26

MPC

0.58

ClinPred

0.031

GERP RS

5.3

Varity_R

0.10

gMVP

0.44

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over