rs117535951

Variant names:

• chr8-144416033-G-A
• rs117535951
• NM_130849.4:c.251C>T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:8
• Conservation: PhyloP100: -0.756
• Publications: 11 publications found

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]

SLC39A4 Gene-Disease associations (from GenCC):

• acrodermatitis enteropathica

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet

LOC124902041 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 362263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SLC39A4	NM_130849.4	c.251C>T	p.Pro84Leu	missense_variant	Exon 2 of 12	ENST00000301305.8	NP_570901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC39A4	ENST00000301305.8	c.251C>T	p.Pro84Leu	missense_variant	Exon 2 of 12	1	NM_130849.4	ENSP00000301305.4
SLC39A4	ENST00000276833.9	c.176C>T	p.Pro59Leu	missense_variant	Exon 1 of 11	2		ENSP00000276833.5
SLC39A4	ENST00000526658.1	c.192+565C>T		intron_variant	Intron 1 of 3	3		ENSP00000434512.1

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

GnomAD2 exomes AF: 0.0289 AC: 5805 AN: 200566 AF XY: 0.0297

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 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

African (AFR) AF: 0.00617 AC: 204 AN: 33088

American (AMR) AF: 0.0183 AC: 753 AN: 41048

Ashkenazi Jewish (ASJ) AF: 0.0577 AC: 1465 AN: 25394

East Asian (EAS) AF: 0.0000518 AC: 2 AN: 38642

South Asian (SAS) AF: 0.00951 AC: 790 AN: 83062

European-Finnish (FIN) AF: 0.0634 AC: 2833 AN: 44718

Middle Eastern (MID) AF: 0.0595 AC: 339 AN: 5700

European-Non Finnish (NFE) AF: 0.0367 AC: 40261 AN: 1096204

Other (OTH) AF: 0.0380 AC: 2243 AN: 59036

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

African (AFR) AF: 0.00684 AC: 284 AN: 41532

American (AMR) AF: 0.0209 AC: 320 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 210 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00828 AC: 40 AN: 4832

European-Finnish (FIN) AF: 0.0643 AC: 683 AN: 10622

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0369 AC: 2507 AN: 67962

Other (OTH) AF: 0.0303 AC: 64 AN: 2112

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary acrodermatitis enteropathica Benign:4

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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:3

Nov 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28188634, 27884173, 12032886, 20981092, 22995991) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.038	.;T
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
MutationAssessor	Benign	1.6	.;L
PhyloP100		-0.76
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
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.032
gMVP		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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