10-17987479-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001145195.2(SLC39A12):c.1097A>C(p.Lys366Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC39A12 NM_001145195.2 missense, splice_region
• Scores: Splicing: ADA: 0.9085
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.83

Genes affected

SLC39A12 (HGNC:20860): (solute carrier family 39 member 12) Zinc is an essential cofactor for hundreds of enzymes. It is involved in protein, nucleic acid, carbohydrate, and lipid metabolism, as well as in the control of gene transcription, growth, development, and differentiation. SLC39A12 belongs to a subfamily of proteins that show structural characteristics of zinc transporters (Taylor and Nicholson, 2003 [PubMed 12659941]).[supplied by OMIM, Aug 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC39A12	NM_001145195.2	c.1097A>C	p.Lys366Thr	missense_variant, splice_region_variant	7/13	ENST00000377369.7
SLC39A12	NM_001282733.2	c.1097A>C	p.Lys366Thr	missense_variant, splice_region_variant	7/13
SLC39A12	NM_152725.4	c.1097A>C	p.Lys366Thr	missense_variant, splice_region_variant	7/12
SLC39A12	NM_001282734.2	c.695A>C	p.Lys232Thr	missense_variant, splice_region_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC39A12	ENST00000377369.7	c.1097A>C	p.Lys366Thr	missense_variant, splice_region_variant	7/13	1	NM_001145195.2	A1
SLC39A12	ENST00000377371.3	c.1097A>C	p.Lys366Thr	missense_variant, splice_region_variant	7/13	1		P4
SLC39A12	ENST00000377374.8	c.1097A>C	p.Lys366Thr	missense_variant, splice_region_variant	7/12	2
SLC39A12	ENST00000539911.5	c.695A>C	p.Lys232Thr	missense_variant, splice_region_variant	6/12	2

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2023

The c.1097A>C (p.K366T) alteration is located in exon 7 (coding exon 6) of the SLC39A12 gene. This alteration results from a A to C substitution at nucleotide position 1097, causing the lysine (K) at amino acid position 366 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	0.23
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Benign	0.17	T;T;T;T
Polyphen		1.0, 1.0, 1.0	.;D;D;D
Vest4		0.82
MutPred		0.44		.;Loss of ubiquitination at K366 (P = 0.0148);Loss of ubiquitination at K366 (P = 0.0148);Loss of ubiquitination at K366 (P = 0.0148);
MVP		0.59
MPC		0.20
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.36
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.13		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: chr10-18276408;