1-153960457-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001271958.2(SLC39A1):c.616C>T(p.Arg206Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,310 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SLC39A1 NM_001271958.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

Genes affected

SLC39A1 (HGNC:12876): (solute carrier family 39 member 1) This gene encodes a member of the zinc-iron permease family. The encoded protein is localized to the cell membrane and acts as a zinc uptake transporter. This gene has been linked to prostate cancer, breast cancer, and Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC39A1	NM_001271958.2	c.616C>T	p.Arg206Trp	missense_variant	4/4	ENST00000356205.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC39A1	ENST00000356205.9	c.616C>T	p.Arg206Trp	missense_variant	4/4	1	NM_001271958.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250154 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461310 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726970

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000630

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

Jun 28, 2023

The c.616C>T (p.R206W) alteration is located in exon 5 (coding exon 3) of the SLC39A1 gene. This alteration results from a C to T substitution at nucleotide position 616, causing the arginine (R) at amino acid position 206 to be replaced by a tryptophan (W). 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	Benign	0.31
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;T;T;T;.;.;.
Eigen	Benign	0.011
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.0098	T
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;L;L;L;L;L;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.61	T
Sift4G	Benign	0.061	T;T;T;T;T;T;T;D;.
Polyphen		0.30	B;B;B;B;B;B;.;.;.
Vest4		0.17
MutPred		0.57		Gain of catalytic residue at A205 (P = 0.0227);Gain of catalytic residue at A205 (P = 0.0227);Gain of catalytic residue at A205 (P = 0.0227);Gain of catalytic residue at A205 (P = 0.0227);Gain of catalytic residue at A205 (P = 0.0227);Gain of catalytic residue at A205 (P = 0.0227);Gain of catalytic residue at A205 (P = 0.0227);Gain of catalytic residue at A205 (P = 0.0227);Gain of catalytic residue at A205 (P = 0.0227);
MVP		0.73
MPC		0.34
ClinPred		0.89	D
GERP RS		3.9
Varity_R		0.24
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs1457926436; hg19: chr1-153932933;