rs117535951

chr8-144416033-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130849.4(SLC39A4):c.251C>T(p.Pro84Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,579,106 control chromosomes in the GnomAD database, including 1,055 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (81 hom., cov: 34)
  • Exomes 𝑓: 0.034 (974 hom.)
• Consequence: SLC39A4 NM_130849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.756

Genes affected

SLC39A4 (HGNC:17129): (solute carrier family 39 member 4) This gene encodes a member of the zinc/iron-regulated transporter-like protein (ZIP) family. The encoded protein localizes to cell membranes and is required for zinc uptake in the intestine. Mutations in this gene result in acrodermatitis enteropathica. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2013]

LOC124902041 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023266077).
• BP6: Variant 8-144416033-G-A is Benign according to our data. Variant chr8-144416033-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 362263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144416033-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC39A4	NM_130849.4	c.251C>T	p.Pro84Leu	missense_variant	2/12	ENST00000301305.8
LOC124902041	XR_007061145.1	n.1502G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC39A4	ENST00000301305.8	c.251C>T	p.Pro84Leu	missense_variant	2/12	1	NM_130849.4	P1
SLC39A4	ENST00000276833.9	c.176C>T	p.Pro59Leu	missense_variant	1/11	2
SLC39A4	ENST00000526658.1	c.192+565C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4148 AN: 152098 Hom.: 80 Cov.: 34

Gnomad AFR AF: 0.00686

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0643

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0369

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0289 AC: 5805 AN: 200566 Hom.: 129 AF XY: 0.0297 AC XY: 3263 AN XY: 109778

Gnomad AFR exome AF: 0.00483

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0571

Gnomad EAS exome AF: 0.0000639

Gnomad SAS exome AF: 0.00987

Gnomad FIN exome AF: 0.0678

Gnomad NFE exome AF: 0.0383

Gnomad OTH exome AF: 0.0336

GnomAD4 exome AF: 0.0343 AC: 48890 AN: 1426892 Hom.: 974 Cov.: 83 AF XY: 0.0338 AC XY: 23893 AN XY: 705994

Gnomad4 AFR exome AF: 0.00617

Gnomad4 AMR exome AF: 0.0183

Gnomad4 ASJ exome AF: 0.0577

Gnomad4 EAS exome AF: 0.0000518

Gnomad4 SAS exome AF: 0.00951

Gnomad4 FIN exome AF: 0.0634

Gnomad4 NFE exome AF: 0.0367

Gnomad4 OTH exome AF: 0.0380

GnomAD4 genome AF: 0.0273 AC: 4148 AN: 152214 Hom.: 81 Cov.: 34 AF XY: 0.0280 AC XY: 2087 AN XY: 74430

Gnomad4 AFR AF: 0.00684

Gnomad4 AMR AF: 0.0209

Gnomad4 ASJ AF: 0.0605

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00828

Gnomad4 FIN AF: 0.0643

Gnomad4 NFE AF: 0.0369

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0359 Hom.: 34

Bravo AF: 0.0236

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0394 AC: 152

ESP6500AA AF: 0.00597 AC: 26

ESP6500EA AF: 0.0353 AC: 301

ExAC AF: 0.0254 AC: 3026

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary acrodermatitis enteropathica Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 25, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Acrodermatitis enteropathica, zinc-deficiency type, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 =>Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	This variant is associated with the following publications: (PMID: 28188634, 27884173, 12032886, 20981092, 22995991) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 44/2178=2% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	4.8
Dann	Benign	0.96
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.61	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.025
Sift	Uncertain	0.019	D;T
Sift4G	Uncertain	0.019	D;D
Polyphen		0.65	.;P
Vest4		0.068
MPC		0.13
ClinPred		0.0015	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.032
gMVP		0.35

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: rs117535951; hg19: chr8-145641417; COSMIC: COSV52781813; COSMIC: COSV52781813;