18-36114372-T-C

Variant names:

• chr18-36114372-T-C
• rs199550071
• NM_012319.4:c.1568A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012319.4(SLC39A6):​c.1568A>G​(p.His523Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,614,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: SLC39A6 NM_012319.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97

Genes affected

SLC39A6 (HGNC:18607): (solute carrier family 39 member 6) 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. SLC39A6 belongs to a subfamily of proteins that show structural characteristics of zinc transporters (Taylor and Nicholson, 2003 [PubMed 12659941]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24048835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC39A6	NM_012319.4	c.1568A>G	p.His523Arg	missense_variant	Exon 7 of 10	ENST00000269187.10	NP_036451.4
SLC39A6	NM_001099406.2	c.743A>G	p.His248Arg	missense_variant	Exon 6 of 8		NP_001092876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC39A6	ENST00000269187.10	c.1568A>G	p.His523Arg	missense_variant	Exon 7 of 10	2	NM_012319.4	ENSP00000269187.4
SLC39A6	ENST00000440549.6	c.743A>G	p.His248Arg	missense_variant	Exon 6 of 8	1		ENSP00000401139.1
SLC39A6	ENST00000590986.5	c.1568A>G	p.His523Arg	missense_variant	Exon 7 of 10	5		ENSP00000465915.1
SLC39A6	ENST00000586829.1	c.269A>G	p.His90Arg	missense_variant	Exon 3 of 5	3		ENSP00000467724.1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000681 AC: 17 AN: 249572 Hom.: 0 AF XY: 0.0000739 AC XY: 10 AN XY: 135402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461886 Hom.: 0 Cov.: 33 AF XY: 0.0000523 AC XY: 38 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152370 Hom.: 0 Cov.: 32 AF XY: 0.0000939 AC XY: 7 AN XY: 74518

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000972 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000909 AC: 11

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1568A>G (p.H523R) alteration is located in exon 7 (coding exon 6) of the SLC39A6 gene. This alteration results from a A to G substitution at nucleotide position 1568, causing the histidine (H) at amino acid position 523 to be replaced by an arginine (R). 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	0.099
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	.;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.7	L;L;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.1	D;.;D;.
REVEL	Uncertain	0.30
Sift	Benign	0.069	T;.;D;.
Sift4G	Uncertain	0.051	T;T;D;T
Polyphen		0.81	P;P;B;.
Vest4		0.14
MutPred		0.60		Gain of loop (P = 0.069);Gain of loop (P = 0.069);.;.;
MVP		0.84
MPC		0.29
ClinPred		0.17	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199550071; hg19: chr18-33694335;