chr4-102253496-T-G

Variant names:

• chr4-102253496-T-G
• rs17032286
• NM_001135147.1:c.1327-66A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001135147.1(SLC39A8):​c.1327-66A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 684,240 control chromosomes in the GnomAD database, including 312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (46 hom., cov: 32)
  • Exomes 𝑓: 0.027 (266 hom.)
• Consequence: SLC39A8 NM_001135147.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0110
• Publications: 2 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 (BayesDel_noAF=-0.9).
• BP6: Variant 4-102253496-T-G is Benign according to our data. Variant chr4-102253496-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1188541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0584 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135147.1. 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_001135147.1		c.1327-66A>C		intron	N/A	NP_001128619.1	Q9C0K1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A8	ENST00000424970.7	TSL:2	n.*299-66A>C		intron	N/A	ENSP00000394548.3	A0A804HKX2

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3357 AN: 152200 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0632

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.0266 AC: 14151 AN: 531922 Hom.: 266 AF XY: 0.0268 AC XY: 7688 AN XY: 287352

African (AFR) AF: 0.00970 AC: 139 AN: 14334

American (AMR) AF: 0.0192 AC: 575 AN: 30018

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 222 AN: 19276

East Asian (EAS) AF: 0.0675 AC: 2031 AN: 30092

South Asian (SAS) AF: 0.0241 AC: 1344 AN: 55678

European-Finnish (FIN) AF: 0.0221 AC: 1068 AN: 48310

Middle Eastern (MID) AF: 0.0335 AC: 132 AN: 3938

European-Non Finnish (NFE) AF: 0.0265 AC: 7986 AN: 301014

Other (OTH) AF: 0.0223 AC: 654 AN: 29262

GnomAD4 genome AF: 0.0220 AC: 3356 AN: 152318 Hom.: 46 Cov.: 32 AF XY: 0.0215 AC XY: 1605 AN XY: 74478

African (AFR) AF: 0.0100 AC: 416 AN: 41568

American (AMR) AF: 0.0271 AC: 415 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.0641 AC: 332 AN: 5180

South Asian (SAS) AF: 0.0234 AC: 113 AN: 4822

European-Finnish (FIN) AF: 0.0170 AC: 181 AN: 10626

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0267 AC: 1819 AN: 68030

Other (OTH) AF: 0.0217 AC: 46 AN: 2116

Alfa AF: 0.0240 Hom.: 73

Bravo AF: 0.0215

Asia WGS AF: 0.0370 AC: 128 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.0
DANN	Benign	0.55
PhyloP100		0.011
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17032286; hg19: chr4-103174653; COSMIC: COSV70574808;