4-102267900-GA-AT

Variant names:

• chr4-102267900-GA-AT
• NM_001135146.2:c.1019_1020delTCinsAT
• SLC39A8 p.Ile340Asn

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS1 PP3

The NM_001135146.2(SLC39A8):​c.1019_1020delTCinsAT​(p.Ile340Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I340M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC39A8 NM_001135146.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.09
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_001135146.2 (SLC39A8) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1019_1020delTCinsAT	p.Ile340Asn	missense	N/A	NP_001128618.1	Q9C0K1-1
	SLC39A8	NM_022154.5		c.1019_1020delTCinsAT	p.Ile340Asn	missense	N/A	NP_071437.3	Q9C0K1-1
	SLC39A8	NM_001135147.1		c.1019_1020delTCinsAT	p.Ile340Asn	missense	N/A	NP_001128619.1	Q9C0K1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A8	ENST00000356736.5	TSL:1 MANE Select	c.1019_1020delTCinsAT	p.Ile340Asn	missense	N/A	ENSP00000349174.4	Q9C0K1-1
	SLC39A8	ENST00000394833.6	TSL:1	c.1019_1020delTCinsAT	p.Ile340Asn	missense	N/A	ENSP00000378310.2	Q9C0K1-1
	SLC39A8	ENST00000856304.1		c.1310_1311delTCinsAT	p.Ile437Asn	missense	N/A	ENSP00000526363.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-103189057;