18-36112579-C-A

Position:

• chr18-36112579-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012319.4(SLC39A6):​c.1846G>T​(p.Ala616Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,460,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC39A6 NM_012319.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A6	NM_012319.4	c.1846G>T	p.Ala616Ser	missense_variant, splice_region_variant	8/10	ENST00000269187.10	NP_036451.4
SLC39A6	NM_001099406.2	c.1021G>T	p.Ala341Ser	missense_variant, splice_region_variant	7/8		NP_001092876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A6	ENST00000269187.10	c.1846G>T	p.Ala616Ser	missense_variant, splice_region_variant	8/10	2	NM_012319.4	ENSP00000269187.4
SLC39A6	ENST00000440549.6	c.1021G>T	p.Ala341Ser	missense_variant, splice_region_variant	7/8	1		ENSP00000401139.1
SLC39A6	ENST00000590986.5	c.1846G>T	p.Ala616Ser	missense_variant, splice_region_variant	8/10	5		ENSP00000465915.1
SLC39A6	ENST00000586829.1	c.547G>T	p.Ala183Ser	missense_variant, splice_region_variant	4/5	3		ENSP00000467724.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460254 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726534

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

May 29, 2024

The c.1846G>T (p.A616S) alteration is located in exon 8 (coding exon 7) of the SLC39A6 gene. This alteration results from a G to T substitution at nucleotide position 1846, causing the alanine (A) at amino acid position 616 to be replaced by a serine (S). 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	0.65
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.9	M;M;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D;.;D;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0060	D;.;D;.
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.66
MutPred		0.80		Gain of disorder (P = 0.0316);Gain of disorder (P = 0.0316);.;.;
MVP		0.61
MPC		2.0
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.45
gMVP		0.85

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-33692542;