chr18-36111249-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_012319.4(SLC39A6):​c.1925G>T​(p.Gly642Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,610,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

SLC39A6
NM_012319.4 missense, splice_region

Scores

14
3
2
Splicing: ADA: 0.9999
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC39A6NM_012319.4 linkuse as main transcriptc.1925G>T p.Gly642Val missense_variant, splice_region_variant 9/10 ENST00000269187.10 NP_036451.4 Q13433-1
SLC39A6NM_001099406.2 linkuse as main transcriptc.1100G>T p.Gly367Val missense_variant, splice_region_variant 8/8 NP_001092876.1 Q13433-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC39A6ENST00000269187.10 linkuse as main transcriptc.1925G>T p.Gly642Val missense_variant, splice_region_variant 9/102 NM_012319.4 ENSP00000269187.4 Q13433-1
SLC39A6ENST00000440549.6 linkuse as main transcriptc.1100G>T p.Gly367Val missense_variant, splice_region_variant 8/81 ENSP00000401139.1 Q13433-2
SLC39A6ENST00000590986.5 linkuse as main transcriptc.1925G>T p.Gly642Val missense_variant, splice_region_variant 9/105 ENSP00000465915.1 Q13433-1
SLC39A6ENST00000586829.1 linkuse as main transcriptc.626G>T p.Gly209Val missense_variant, splice_region_variant 5/53 ENSP00000467724.1 K7EQ91

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152056
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000809
AC:
2
AN:
247112
Hom.:
0
AF XY:
0.0000149
AC XY:
2
AN XY:
134018
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000254
AC:
37
AN:
1458420
Hom.:
0
Cov.:
31
AF XY:
0.0000193
AC XY:
14
AN XY:
725100
show subpopulations
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:
0.0000324
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152056
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74270
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2023The c.1925G>T (p.G642V) alteration is located in exon 9 (coding exon 8) of the SLC39A6 gene. This alteration results from a G to T substitution at nucleotide position 1925, causing the glycine (G) at amino acid position 642 to be replaced by a valine (V). 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
1.0
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
T;T;.;.
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D;D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Uncertain
0.042
D
MutationAssessor
Pathogenic
3.8
H;H;.;.
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-8.7
D;.;D;.
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D;.;D;.
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;D;.
Vest4
0.99
MutPred
0.92
Loss of catalytic residue at P638 (P = 0.0741);Loss of catalytic residue at P638 (P = 0.0741);.;.;
MVP
0.95
MPC
2.4
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.92
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763112204; hg19: chr18-33691212; API