4-102344566-C-T

Position:

• chr4-102344566-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_001135146.2(SLC39A8):​c.97G>A​(p.Val33Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 1,552,182 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V33V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00045 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: SLC39A8 NM_001135146.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.913

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012170166).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000453 (69/152282) while in subpopulation SAS AF= 0.00124 (6/4834). AF 95% confidence interval is 0.00054. There are 1 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC39A8	NM_001135146.2	c.97G>A	p.Val33Met	missense_variant	2/9	ENST00000356736.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC39A8	ENST00000356736.5	c.97G>A	p.Val33Met	missense_variant	2/9	1	NM_001135146.2	P1

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000642 AC: 97 AN: 151170 Hom.: 0 AF XY: 0.000690 AC XY: 56 AN XY: 81190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000672

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000694 AC: 971 AN: 1399900 Hom.: 1 Cov.: 30 AF XY: 0.000735 AC XY: 508 AN XY: 690842

Gnomad4 AFR exome AF: 0.0000318

Gnomad4 AMR exome AF: 0.000831

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.0000411

Gnomad4 NFE exome AF: 0.000739

Gnomad4 OTH exome AF: 0.000310

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74452

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000385 Hom.: 0

Bravo AF: 0.000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000238 AC: 1

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000329 AC: 35

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2023	Identified in a patient with impaired glycosylation, global psychomotor delay, epilepsy, cerebellar atrophy, hypotonia, scoliosis, and low manganese concentrations who also harbored a SLC39A8 variant in cis and another SLC39A8 variant in trans (Park et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32753748, 35636252, 29453449, 26637979) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 19, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.84	T;.;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.90	L;L;L
MutationTaster	Benign	0.90	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		0.72	.;P;P
Vest4		0.24
MVP		0.11
MPC		0.89
ClinPred		0.093	T
GERP RS		2.8
Varity_R		0.15
gMVP		0.59

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: rs373562040; hg19: chr4-103265723;