18-36111192-T-A

Position:

• chr18-36111192-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012319.4(SLC39A6):​c.1982A>T​(p.Asn661Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC39A6 NM_012319.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

SLC39A6 (HGNC:18607): (solute carrier family 39 member 6) Zinc is an essential cofactor for hundreds of enzymes. It is involved in protein, nucleic acid, carbohydrate, and lipid metabolism, as well as in the control of gene transcription, growth, development, and differentiation. SLC39A6 belongs to a subfamily of proteins that show structural characteristics of zinc transporters (Taylor and Nicholson, 2003 [PubMed 12659941]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A6	NM_012319.4	c.1982A>T	p.Asn661Ile	missense_variant	9/10	ENST00000269187.10	NP_036451.4
SLC39A6	NM_001099406.2	c.1157A>T	p.Asn386Ile	missense_variant	8/8		NP_001092876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A6	ENST00000269187.10	c.1982A>T	p.Asn661Ile	missense_variant	9/10	2	NM_012319.4	ENSP00000269187.4
SLC39A6	ENST00000440549.6	c.1157A>T	p.Asn386Ile	missense_variant	8/8	1		ENSP00000401139.1
SLC39A6	ENST00000590986.5	c.1982A>T	p.Asn661Ile	missense_variant	9/10	5		ENSP00000465915.1
SLC39A6	ENST00000586829.1	c.683A>T	p.Asn228Ile	missense_variant	5/5	3		ENSP00000467724.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.1982A>T (p.N661I) alteration is located in exon 9 (coding exon 8) of the SLC39A6 gene. This alteration results from a A to T substitution at nucleotide position 1982, causing the asparagine (N) at amino acid position 661 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.6	H;H;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.8	D;.;D;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.96
MutPred		0.81		Gain of catalytic residue at A665 (P = 0.1713);Gain of catalytic residue at A665 (P = 0.1713);.;.;
MVP		0.75
MPC		2.4
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.89
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-33691155;