12-56231284-T-C

Position:

• chr12-56231284-T-C

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.10T>C​(p.Ser4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,605,402 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (15 hom.)
• Consequence: SLC39A5 NM_173596.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.40

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=0.0020042956).
• BP6: Variant 12-56231284-T-C is Benign according to our data. Variant chr12-56231284-T-C is described in ClinVar as [Benign]. Clinvar id is 776719.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 = 0.00713 (1084/152112) while in subpopulation AFR AF= 0.0248 (1029/41520). AF 95% confidence interval is 0.0235. There are 20 homozygotes in gnomad4. There are 539 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1084 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A5	NM_173596.3	c.10T>C	p.Ser4Pro	missense_variant	4/13	ENST00000454355.7	NP_775867.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A5	ENST00000454355.7	c.10T>C	p.Ser4Pro	missense_variant	4/13	1	NM_173596.3	ENSP00000405360	P1

Frequencies

GnomAD3 genomes AF: 0.00715 AC: 1086 AN: 151994 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00174 AC: 421 AN: 242598 Hom.: 7 AF XY: 0.00128 AC XY: 168 AN XY: 131744

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.000974

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: 0.0000276

Gnomad OTH exome AF: 0.000338

GnomAD4 exome AF: 0.000680 AC: 988 AN: 1453290 Hom.: 15 Cov.: 34 AF XY: 0.000594 AC XY: 429 AN XY: 722226

Gnomad4 AFR exome AF: 0.0256

Gnomad4 AMR exome AF: 0.00111

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000819

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000813

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00713 AC: 1084 AN: 152112 Hom.: 20 Cov.: 32 AF XY: 0.00725 AC XY: 539 AN XY: 74350

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00392 Hom.: 2

Bravo AF: 0.00799

ESP6500AA AF: 0.0184 AC: 80

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00204 AC: 247

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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	May 20, 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	0.056
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	1.4
DANN	Benign	0.65
DEOGEN2	Benign	0.0037	.;T;T;.;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.47	T;T;.;T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.64	.;.;N;.;.;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.070	N;N;N;N;N;N;N
REVEL	Benign	0.057
Sift	Benign	1.0	T;T;T;T;D;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;.;.;B;.
Vest4		0.032, 0.036
MVP		0.16
MPC		0.15
ClinPred		0.0063	T
GERP RS		-4.8
Varity_R		0.060
gMVP		0.29

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: rs116413529; hg19: chr12-56625068;