rs2478568

Positions:

• chr10-17978060-G-A
• chr10-17978060-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001145195.2(SLC39A12):​c.910G>A​(p.Val304Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 1,587,006 control chromosomes in the GnomAD database, including 332,722 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.65 (31714 hom., cov: 33)
  • Exomes 𝑓: 0.65 (301008 hom.)
• Consequence: SLC39A12 NM_001145195.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.02

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3368938E-6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A12	NM_001145195.2	c.910G>A	p.Val304Ile	missense_variant	5/13	ENST00000377369.7	NP_001138667.1
SLC39A12	NM_001282733.2	c.910G>A	p.Val304Ile	missense_variant	5/13		NP_001269662.1
SLC39A12	NM_152725.4	c.910G>A	p.Val304Ile	missense_variant	5/12		NP_689938.2
SLC39A12	NM_001282734.2	c.508G>A	p.Val170Ile	missense_variant	4/12		NP_001269663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A12	ENST00000377369.7	c.910G>A	p.Val304Ile	missense_variant	5/13	1	NM_001145195.2	ENSP00000366586	A1
SLC39A12	ENST00000377371.3	c.910G>A	p.Val304Ile	missense_variant	5/13	1		ENSP00000366588	P4
SLC39A12	ENST00000377374.8	c.910G>A	p.Val304Ile	missense_variant	5/12	2		ENSP00000366591
SLC39A12	ENST00000539911.5	c.508G>A	p.Val170Ile	missense_variant	4/12	2		ENSP00000440445

Frequencies

GnomAD3 genomes AF: 0.645 AC: 98023 AN: 151974 Hom.: 31677 Cov.: 33

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.732

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.643

GnomAD3 exomes AF: 0.657 AC: 152222 AN: 231600 Hom.: 50400 AF XY: 0.660 AC XY: 83016 AN XY: 125822

Gnomad AFR exome AF: 0.624

Gnomad AMR exome AF: 0.682

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.663

Gnomad SAS exome AF: 0.729

Gnomad FIN exome AF: 0.691

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.646 AC: 927456 AN: 1434914 Hom.: 301008 Cov.: 34 AF XY: 0.648 AC XY: 462645 AN XY: 713418

Gnomad4 AFR exome AF: 0.633

Gnomad4 AMR exome AF: 0.677

Gnomad4 ASJ exome AF: 0.608

Gnomad4 EAS exome AF: 0.646

Gnomad4 SAS exome AF: 0.729

Gnomad4 FIN exome AF: 0.687

Gnomad4 NFE exome AF: 0.638

Gnomad4 OTH exome AF: 0.651

GnomAD4 genome AF: 0.645 AC: 98105 AN: 152092 Hom.: 31714 Cov.: 33 AF XY: 0.650 AC XY: 48301 AN XY: 74346

Gnomad4 AFR AF: 0.626

Gnomad4 AMR AF: 0.674

Gnomad4 ASJ AF: 0.607

Gnomad4 EAS AF: 0.665

Gnomad4 SAS AF: 0.732

Gnomad4 FIN AF: 0.691

Gnomad4 NFE AF: 0.637

Gnomad4 OTH AF: 0.648

Alfa AF: 0.638 Hom.: 79896

Bravo AF: 0.640

TwinsUK AF: 0.639 AC: 2370

ALSPAC AF: 0.653 AC: 2518

ESP6500AA AF: 0.626 AC: 2758

ESP6500EA AF: 0.632 AC: 5431

ExAC AF: 0.658 AC: 79916

Asia WGS AF: 0.725 AC: 2523 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.0010
DANN	Benign	0.40
DEOGEN2	Benign	0.00025	.;T;.;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.050	T;T;T;T
MetaRNN	Benign	0.0000013	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.85	.;N;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.16	N;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.24	T;T;T;T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		0.0	.;B;B;B
Vest4		0.048
MPC		0.022
ClinPred		0.035	T
GERP RS		-9.4
Varity_R		0.042
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2478568; hg19: chr10-18266989; COSMIC: COSV101070232;