rs112519623

Variant names:

• chr4-102263082-G-A
• rs112519623
• NM_001135146.2:c.1345C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001135146.2(SLC39A8):​c.1345C>T​(p.Leu449Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,476 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 33)
  • Exomes 𝑓: 0.013 (182 hom.)
• Consequence: SLC39A8 NM_001135146.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.56
• Publications: 16 publications found

Genes affected

SLC39A8 (HGNC:20862): (solute carrier family 39 member 8) This gene encodes a member of the SLC39 family of solute-carrier genes, which show structural characteristics of zinc transporters. The encoded protein is glycosylated and found in the plasma membrane and mitochondria, and functions in the cellular import of zinc at the onset of inflammation. It is also thought to be the primary transporter of the toxic cation cadmium, which is found in cigarette smoke. Multiple transcript variants encoding different isoforms have been found for this gene. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Oct 2008]

SLC39A8 Gene-Disease associations (from GenCC):

• SLC39A8-CDG

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009424508).
• BP6: Variant 4-102263082-G-A is Benign according to our data. Variant chr4-102263082-G-A is described in ClinVar as Benign. ClinVar VariationId is 1660980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0103 (1572/152298) while in subpopulation NFE AF = 0.0156 (1059/68018). AF 95% confidence interval is 0.0148. There are 11 homozygotes in GnomAd4. There are 730 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135146.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A8	NM_001135146.2	MANE Select	c.1345C>T	p.Leu449Phe	missense	Exon 9 of 9	NP_001128618.1	Q9C0K1-1
	SLC39A8	NM_022154.5		c.1345C>T	p.Leu449Phe	missense	Exon 8 of 8	NP_071437.3	Q9C0K1-1
	SLC39A8	NM_001135148.2		c.1144C>T	p.Leu382Phe	missense	Exon 8 of 8	NP_001128620.1	Q9C0K1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A8	ENST00000356736.5	TSL:1 MANE Select	c.1345C>T	p.Leu449Phe	missense	Exon 9 of 9	ENSP00000349174.4	Q9C0K1-1
	SLC39A8	ENST00000394833.6	TSL:1	c.1345C>T	p.Leu449Phe	missense	Exon 8 of 8	ENSP00000378310.2	Q9C0K1-1
	SLC39A8	ENST00000856304.1		c.1636C>T	p.Leu546Phe	missense	Exon 10 of 10	ENSP00000526363.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1574 AN: 152180 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0107 AC: 2684 AN: 251020 AF XY: 0.0101

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.00849

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0194

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0134 AC: 19630 AN: 1461178 Hom.: 182 Cov.: 32 AF XY: 0.0129 AC XY: 9364 AN XY: 726922

African (AFR) AF: 0.00194 AC: 65 AN: 33454

American (AMR) AF: 0.00886 AC: 396 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 82 AN: 26110

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39666

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86178

European-Finnish (FIN) AF: 0.0209 AC: 1112 AN: 53308

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0156 AC: 17350 AN: 1111626

Other (OTH) AF: 0.0103 AC: 620 AN: 60366

GnomAD4 genome AF: 0.0103 AC: 1572 AN: 152298 Hom.: 11 Cov.: 33 AF XY: 0.00980 AC XY: 730 AN XY: 74452

African (AFR) AF: 0.00291 AC: 121 AN: 41580

American (AMR) AF: 0.00706 AC: 108 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0193 AC: 205 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0156 AC: 1059 AN: 68018

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0133 Hom.: 54

Bravo AF: 0.00940

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0153 AC: 132

ExAC AF: 0.0110 AC: 1337

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0122

EpiControl AF: 0.0130

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.23	T
Polyphen		0.93	P
Vest4		0.18
MPC		1.4
ClinPred		0.028	T
GERP RS		4.8
Varity_R		0.35
gMVP		0.84
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs112519623; hg19: chr4-103184239; COSMIC: COSV108175167;