12-56232789-C-T

Position:

• chr12-56232789-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173596.3(SLC39A5):​c.388C>T​(p.Arg130Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0014 in 1,612,570 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (19 hom., cov: 30)
  • Exomes 𝑓: 0.00078 (19 hom.)
• Consequence: SLC39A5 NM_173596.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.03

Genes affected

SLC39A5 (HGNC:20502): (solute carrier family 39 member 5) The protein encoded by this gene belongs to the ZIP family of zinc transporters that transport zinc into cells from outside, and play a crucial role in controlling intracellular zinc levels. Zinc is an essential cofactor for many enzymes and proteins involved in gene transcription, growth, development and differentiation. Mutations in this gene have been associated with autosomal dominant high myopia (MYP24). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049285293).
• BP6: Variant 12-56232789-C-T is Benign according to our data. Variant chr12-56232789-C-T is described in ClinVar as [Benign]. Clinvar id is 785411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00741 (1129/152280) while in subpopulation AFR AF= 0.0257 (1068/41560). AF 95% confidence interval is 0.0244. There are 19 homozygotes in gnomad4. There are 542 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1129 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A5	NM_173596.3	c.388C>T	p.Arg130Cys	missense_variant	5/13	ENST00000454355.7	NP_775867.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A5	ENST00000454355.7	c.388C>T	p.Arg130Cys	missense_variant	5/13	1	NM_173596.3	ENSP00000405360	P1

Frequencies

GnomAD3 genomes AF: 0.00741 AC: 1127 AN: 152162 Hom.: 19 Cov.: 30

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00196 AC: 488 AN: 249112 Hom.: 7 AF XY: 0.00144 AC XY: 194 AN XY: 134876

Gnomad AFR exome AF: 0.0276

Gnomad AMR exome AF: 0.000973

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000987

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000777 AC: 1134 AN: 1460290 Hom.: 19 Cov.: 31 AF XY: 0.000626 AC XY: 455 AN XY: 726574

Gnomad4 AFR exome AF: 0.0281

Gnomad4 AMR exome AF: 0.00111

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00153

GnomAD4 genome AF: 0.00741 AC: 1129 AN: 152280 Hom.: 19 Cov.: 30 AF XY: 0.00728 AC XY: 542 AN XY: 74456

Gnomad4 AFR AF: 0.0257

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.00833

ESP6500AA AF: 0.0263 AC: 116

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00249 AC: 302

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T;T;T;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T;.;T;T
MetaRNN	Benign	0.0049	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	.;L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.0	D;N;D;N
REVEL	Benign	0.17
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		0.95	.;P;.;P
Vest4		0.22, 0.22
MVP		0.21
MPC		0.48
ClinPred		0.065	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
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

Other links and lift over

dbSNP: rs76909887; hg19: chr12-56626573; COSMIC: COSV57191538; COSMIC: COSV57191538;