1-37815194-A-G

Variant names:

• chr1-37815194-A-G
• rs201482284
• NM_005955.3:c.2204T>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005955.3(MTF1):​c.2204T>C​(p.Ile735Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000384 in 1,614,016 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. I735N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: MTF1 NM_005955.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16163975).
• BS2: High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTF1	NM_005955.3	c.2204T>C	p.Ile735Thr	missense_variant	Exon 11 of 11	ENST00000373036.5	NP_005946.2
MTF1	XM_011541491.3	c.2204T>C	p.Ile735Thr	missense_variant	Exon 11 of 11		XP_011539793.1
MTF1	XM_047421170.1	c.2204T>C	p.Ile735Thr	missense_variant	Exon 12 of 12		XP_047277126.1
MTF1	XM_047421173.1	c.1277T>C	p.Ile426Thr	missense_variant	Exon 10 of 10		XP_047277129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTF1	ENST00000373036.5	c.2204T>C	p.Ile735Thr	missense_variant	Exon 11 of 11	1	NM_005955.3	ENSP00000362127.3

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000318 AC: 80 AN: 251488 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135918

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000563

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000403 AC: 589 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.000393 AC XY: 286 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000482

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74306

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000508 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2204T>C (p.I735T) alteration is located in exon 11 (coding exon 10) of the MTF1 gene. This alteration results from a T to C substitution at nucleotide position 2204, causing the isoleucine (I) at amino acid position 735 to be replaced by a threonine (T). 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	0.22
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.073
Eigen_PC	Benign	0.057
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.0	B
Vest4		0.62
MVP		0.15
MPC		0.84
ClinPred		0.077	T
GERP RS		3.4
Varity_R		0.15
gMVP		0.52

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

Other links and lift over

dbSNP: rs201482284; hg19: chr1-38280866; COSMIC: COSV100888659;