12-56231330-T-C

Position:

• chr12-56231330-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_173596.3(SLC39A5):​c.56T>C​(p.Leu19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,613,412 control chromosomes in the GnomAD database, including 50 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 0.0043 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (48 hom.)
• Consequence: SLC39A5 NM_173596.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.57

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006154835).
• BP6: Variant 12-56231330-T-C is Benign according to our data. Variant chr12-56231330-T-C is described in ClinVar as [Benign]. Clinvar id is 768554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56231330-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 657 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A5	NM_173596.3	c.56T>C	p.Leu19Ser	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.56T>C	p.Leu19Ser	missense_variant	4/13	1	NM_173596.3	ENSP00000405360	P1

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 657 AN: 152130 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00606

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00549 AC: 1370 AN: 249382 Hom.: 11 AF XY: 0.00591 AC XY: 798 AN XY: 135112

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00872

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00759

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.00661

Gnomad OTH exome AF: 0.00493

GnomAD4 exome AF: 0.00666 AC: 9726 AN: 1461164 Hom.: 48 Cov.: 34 AF XY: 0.00674 AC XY: 4896 AN XY: 726898

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00793

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00837

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.00704

Gnomad4 OTH exome AF: 0.00447

GnomAD4 genome AF: 0.00432 AC: 657 AN: 152248 Hom.: 2 Cov.: 32 AF XY: 0.00449 AC XY: 334 AN XY: 74444

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00951

Gnomad4 NFE AF: 0.00606

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00625 Hom.: 8

Bravo AF: 0.00382

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00547 AC: 664

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00622

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	SLC39A5: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 24, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.012	.;T;T;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.51	T;T;.;T;T;T
MetaRNN	Benign	0.0062	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;.;L;.;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.65	N;N;N;N;N;N
REVEL	Benign	0.059
Sift	Benign	0.057	T;T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T;T
Polyphen		0.0060	.;.;B;.;B;.
Vest4		0.48, 0.49
MVP		0.092
MPC		0.17
ClinPred		0.0063	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147572362; hg19: chr12-56625114;