NM_001301267.2:c.29-2A>T

Variant names:

• chr16-56667382-T-A
• rs2298847
• NM_001301267.2:c.29-2A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The NM_001301267.2(MT1G):​c.29-2A>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,798 control chromosomes in the GnomAD database, including 19,757 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2309 hom., cov: 33)
  • Exomes 𝑓: 0.14 (17448 hom.)
• Consequence: MT1G NM_001301267.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.00001695
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11
• Publications: 15 publications found

Genes affected

MT1G (HGNC:7399): (metallothionein 1G) Enables zinc ion binding activity. Involved in cellular response to metal ion; cellular response to vascular endothelial growth factor stimulus; and negative regulation of growth. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.36507937 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of 3, new splice context is: ggctttttctcttcttgcAGgtg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MT1G	NM_001301267.2	c.29-2A>T		splice_acceptor_variant, intron_variant	Intron 1 of 2	ENST00000379811.4	NP_001288196.1
MT1G	NM_005950.3	c.29-5A>T		splice_region_variant, intron_variant	Intron 1 of 2		NP_005941.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT1G	ENST00000379811.4	c.29-2A>T		splice_acceptor_variant, intron_variant	Intron 1 of 2	1	NM_001301267.2	ENSP00000369139.4
MT1G	ENST00000444837.6	c.29-5A>T		splice_region_variant, intron_variant	Intron 1 of 2	1		ENSP00000391397.2
MT1G	ENST00000568675.1	n.57-5A>T		splice_region_variant, intron_variant	Intron 1 of 1	1
MT1G	ENST00000569500.5	c.29-412A>T		intron_variant	Intron 1 of 1	3		ENSP00000456675.1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23407 AN: 152028 Hom.: 2308 Cov.: 33

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.151

GnomAD2 exomes AF: 0.191 AC: 47948 AN: 251082 AF XY: 0.183

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.396

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.420

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.136 AC: 198273 AN: 1461652 Hom.: 17448 Cov.: 32 AF XY: 0.137 AC XY: 99600 AN XY: 727122

African (AFR) AF: 0.149 AC: 4982 AN: 33476

American (AMR) AF: 0.381 AC: 17014 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3682 AN: 26128

East Asian (EAS) AF: 0.381 AC: 15130 AN: 39690

South Asian (SAS) AF: 0.236 AC: 20317 AN: 86234

European-Finnish (FIN) AF: 0.106 AC: 5652 AN: 53386

Middle Eastern (MID) AF: 0.137 AC: 790 AN: 5768

European-Non Finnish (NFE) AF: 0.109 AC: 121655 AN: 1111920

Other (OTH) AF: 0.150 AC: 9051 AN: 60390

GnomAD4 genome AF: 0.154 AC: 23425 AN: 152146 Hom.: 2309 Cov.: 33 AF XY: 0.160 AC XY: 11894 AN XY: 74382

African (AFR) AF: 0.151 AC: 6268 AN: 41506

American (AMR) AF: 0.285 AC: 4350 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 514 AN: 3468

East Asian (EAS) AF: 0.413 AC: 2128 AN: 5154

South Asian (SAS) AF: 0.233 AC: 1120 AN: 4814

European-Finnish (FIN) AF: 0.104 AC: 1104 AN: 10612

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7514 AN: 67982

Other (OTH) AF: 0.154 AC: 325 AN: 2116

Alfa AF: 0.121 Hom.: 401

Bravo AF: 0.167

TwinsUK AF: 0.0976 AC: 362

ALSPAC AF: 0.109 AC: 419

ESP6500AA AF: 0.155 AC: 682

ESP6500EA AF: 0.115 AC: 988

ExAC AF: 0.182 AC: 22120

Asia WGS AF: 0.296 AC: 1031 AN: 3478

EpiCase AF: 0.109

EpiControl AF: 0.111

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.0
DANN	Benign	0.53
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.0074	N
PhyloP100		-1.1
GERP RS		-1.9
Mutation Taster		=76/24	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: 23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2298847; hg19: chr16-56701294; COSMIC: COSV60090662; COSMIC: COSV60090662;