1-37815194-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005955.3(MTF1):​c.2204T>A​(p.Ile735Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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. I735T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28893894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTF1	NM_005955.3	c.2204T>A	p.Ile735Asn	missense_variant	Exon 11 of 11	ENST00000373036.5	NP_005946.2
MTF1	XM_011541491.3	c.2204T>A	p.Ile735Asn	missense_variant	Exon 11 of 11		XP_011539793.1
MTF1	XM_047421170.1	c.2204T>A	p.Ile735Asn	missense_variant	Exon 12 of 12		XP_047277126.1
MTF1	XM_047421173.1	c.1277T>A	p.Ile426Asn	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>A	p.Ile735Asn	missense_variant	Exon 11 of 11	1	NM_005955.3	ENSP00000362127.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2204T>A (p.I735N) alteration is located in exon 11 (coding exon 10) of the MTF1 gene. This alteration results from a T to A substitution at nucleotide position 2204, causing the isoleucine (I) at amino acid position 735 to be replaced by an asparagine (N). 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	Pathogenic	0.60
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	-0.016
Eigen_PC	Benign	0.097
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.15	B
Vest4		0.66
MutPred		0.18		Gain of loop (P = 0.1081);
MVP		0.12
MPC		1.0
ClinPred		0.69	D
GERP RS		3.4
Varity_R		0.31
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-38280866;