4-102263082-G-A

Position:

• chr4-102263082-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A8	NM_001135146.2	c.1345C>T	p.Leu449Phe	missense_variant	9/9	ENST00000356736.5	NP_001128618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A8	ENST00000356736.5	c.1345C>T	p.Leu449Phe	missense_variant	9/9	1	NM_001135146.2	ENSP00000349174.4

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

GnomAD3 exomes AF: 0.0107 AC: 2684 AN: 251020 Hom.: 26 AF XY: 0.0101 AC XY: 1371 AN XY: 135702

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.00886

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0209

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0103

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

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0193

Gnomad4 NFE AF: 0.0156

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0131 Hom.: 18

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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;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;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.23	T;T
Polyphen		0.93	P;P
Vest4		0.18
MPC		1.4
ClinPred		0.028	T
GERP RS		4.8
Varity_R		0.35
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs112519623; hg19: chr4-103184239;