chr4-102263142-C-A

Variant names:

• chr4-102263142-C-A
• rs780090155
• NM_001135146.2:c.1285G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001135146.2(SLC39A8):​c.1285G>T​(p.Asp429Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D429D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SLC39A8 NM_001135146.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1285G>T	p.Asp429Tyr	missense	Exon 9 of 9	NP_001128618.1	Q9C0K1-1
	SLC39A8	NM_022154.5		c.1285G>T	p.Asp429Tyr	missense	Exon 8 of 8	NP_071437.3	Q9C0K1-1
	SLC39A8	NM_001135148.2		c.1084G>T	p.Asp362Tyr	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.1285G>T	p.Asp429Tyr	missense	Exon 9 of 9	ENSP00000349174.4	Q9C0K1-1
	SLC39A8	ENST00000394833.6	TSL:1	c.1285G>T	p.Asp429Tyr	missense	Exon 8 of 8	ENSP00000378310.2	Q9C0K1-1
	SLC39A8	ENST00000856304.1		c.1576G>T	p.Asp526Tyr	missense	Exon 10 of 10	ENSP00000526363.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251170 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461482 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727042

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111752

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.047	D
Polyphen		0.96	D
Vest4		0.59
MutPred		0.63		Gain of glycosylation at T424 (P = 0.0083)
MVP		0.45
MPC		1.5
ClinPred		0.72	D
GERP RS		5.7
Varity_R		0.61
gMVP		0.69
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780090155; hg19: chr4-103184299;