Genetic Variant SLC39A1:p.Gly265Arg (chr1-153960280-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001271958.2(SLC39A1):c.793G>A(p.Gly265Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000843 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

SLC39A1
NM_001271958.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.70

Variant links:

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]

SLC39A1 links:

ENSG00000285779 (HGNC:):

ENSG00000285779 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.038847446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC39A1	NM_001271958.2 link	c.793G>A	p.Gly265Arg	missense_variant	Exon 4 of 4	ENST00000356205.9	NP_001258887.1	Q9NY26-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC39A1	ENST00000356205.9 link	c.793G>A	p.Gly265Arg	missense_variant	Exon 4 of 4	1	NM_001271958.2	ENSP00000348535.4	Q9NY26-1
ENSG00000285779	ENST00000648921.1 link	n.*881G>A		non_coding_transcript_exon_variant	Exon 6 of 6			ENSP00000498105.1	A0A3B3ITX8
ENSG00000285779	ENST00000648921.1 link	n.*881G>A		3_prime_UTR_variant	Exon 6 of 6			ENSP00000498105.1	A0A3B3ITX8

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00115

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:

0.000478

GnomAD3 exomes

AF:

0.000144

AC:

AN:

250800

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000773

AC:

113

AN:

1461732

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00272

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000151

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000293

Hom.:

Bravo

AF:

0.000310

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.793G>A (p.G265R) alteration is located in exon 5 (coding exon 3) of the SLC39A1 gene. This alteration results from a G to A substitution at nucleotide position 793, causing the glycine (G) at amino acid position 265 to be replaced by an arginine (R). 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.19

T;T;T;T;T;T;.

Eigen

Benign

-0.023

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.86

.;.;D;.;.;.;D

M_CAP

Benign

0.0091

MetaRNN

Benign

0.039

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.41

N;N;N;N;N;N;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.1

.;N;.;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.087

.;T;.;T;T;T;T

Sift4G

Benign

0.52

T;T;T;T;T;T;T

Polyphen

0.061

B;B;B;B;B;B;.

Vest4

0.36

MutPred

0.62

Gain of solvent accessibility (P = 0.0128);Gain of solvent accessibility (P = 0.0128);Gain of solvent accessibility (P = 0.0128);Gain of solvent accessibility (P = 0.0128);Gain of solvent accessibility (P = 0.0128);Gain of solvent accessibility (P = 0.0128);Gain of solvent accessibility (P = 0.0128);

MVP

0.50

MPC

0.58

ClinPred

0.073

GERP RS

5.4

Varity_R

0.068

gMVP

0.46

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over