1-37815464-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005955.3(MTF1):​c.1934G>A​(p.Arg645Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,603,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. R645W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MTF1
NM_005955.3 missense

Scores

5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.08660206).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MTF1NM_005955.3 linkc.1934G>A p.Arg645Gln missense_variant Exon 11 of 11 ENST00000373036.5 NP_005946.2 Q14872
MTF1XM_011541491.3 linkc.1934G>A p.Arg645Gln missense_variant Exon 11 of 11 XP_011539793.1 Q14872
MTF1XM_047421170.1 linkc.1934G>A p.Arg645Gln missense_variant Exon 12 of 12 XP_047277126.1
MTF1XM_047421173.1 linkc.1007G>A p.Arg336Gln missense_variant Exon 10 of 10 XP_047277129.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MTF1ENST00000373036.5 linkc.1934G>A p.Arg645Gln missense_variant Exon 11 of 11 1 NM_005955.3 ENSP00000362127.3 Q14872

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000415
AC:
1
AN:
241082
Hom.:
0
AF XY:
0.00000767
AC XY:
1
AN XY:
130332
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000918
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1451840
Hom.:
0
Cov.:
31
AF XY:
0.00000831
AC XY:
6
AN XY:
721634
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000397
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152088
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74272
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 27, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1934G>A (p.R645Q) alteration is located in exon 11 (coding exon 10) of the MTF1 gene. This alteration results from a G to A substitution at nucleotide position 1934, causing the arginine (R) at amino acid position 645 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Uncertain
24
DANN
Uncertain
1.0
Eigen
Benign
0.16
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.88
D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.087
T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
0.69
N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
0.34
N
REVEL
Benign
0.088
Sift
Uncertain
0.017
D
Sift4G
Benign
0.24
T
Polyphen
0.33
B
Vest4
0.14
MutPred
0.14
Loss of MoRF binding (P = 0.0471);
MVP
0.45
MPC
0.26
ClinPred
0.63
D
GERP RS
6.0
Varity_R
0.059
gMVP
0.071

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs948918089; hg19: chr1-38281136; API