chr18-36111060-A-G

Position:

• chr18-36111060-A-G

Variant summary

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

The NM_012319.4(SLC39A6):​c.2114T>C​(p.Met705Thr) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC39A6 NM_012319.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A6	NM_012319.4	c.2114T>C	p.Met705Thr	missense_variant, splice_region_variant	9/10	ENST00000269187.10	NP_036451.4
SLC39A6	NM_001099406.2	c.1289T>C	p.Met430Thr	missense_variant	8/8		NP_001092876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A6	ENST00000440549.6	c.1289T>C	p.Met430Thr	missense_variant	8/8	1		ENSP00000401139.1
SLC39A6	ENST00000269187.10	c.2114T>C	p.Met705Thr	missense_variant, splice_region_variant	9/10	2	NM_012319.4	ENSP00000269187.4
SLC39A6	ENST00000586829.1	c.815T>C	p.Met272Thr	missense_variant	5/5	3		ENSP00000467724.1
SLC39A6	ENST00000590986.5	c.2114T>C	p.Met705Thr	missense_variant, splice_region_variant	9/10	5		ENSP00000465915.1

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

Nov 07, 2024

The c.2114T>C (p.M705T) alteration is located in exon 9 (coding exon 8) of the SLC39A6 gene. This alteration results from a T to C substitution at nucleotide position 2114, causing the methionine (M) at amino acid position 705 to be replaced by a threonine (T). 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	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;T;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.6	H;H;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.8	D;.;D;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.97	D;D;D;.
Vest4		0.93
MutPred		0.74		Loss of stability (P = 0.011);Loss of stability (P = 0.011);.;.;
MVP		0.87
MPC		2.3
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr18-33691023;