rs17855765

chr8-144415944-C-T

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.340G>A(p.Ala114Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 1,591,926 control chromosomes in the GnomAD database, including 195,443 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15453 hom., cov: 33)
  • Exomes 𝑓: 0.50 (179990 hom.)
• Consequence: SLC39A4 NM_130849.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.383

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=1.969787E-5).
• BP6: Variant 8-144415944-C-T is Benign according to our data. Variant chr8-144415944-C-T is described in ClinVar as [Benign]. Clinvar id is 362260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144415944-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC39A4	NM_130849.4	c.340G>A	p.Ala114Thr	missense_variant	2/12	ENST00000301305.8
LOC124902041	XR_007061145.1	n.1413C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC39A4	ENST00000301305.8	c.340G>A	p.Ala114Thr	missense_variant	2/12	1	NM_130849.4	P1
SLC39A4	ENST00000276833.9	c.265G>A	p.Ala89Thr	missense_variant	1/11	2
SLC39A4	ENST00000526658.1	c.193-525G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66765 AN: 151934 Hom.: 15455 Cov.: 33

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.446

GnomAD3 exomes AF: 0.458 AC: 97205 AN: 212328 Hom.: 22840 AF XY: 0.464 AC XY: 53849 AN XY: 116026

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.595

Gnomad EAS exome AF: 0.368

Gnomad SAS exome AF: 0.391

Gnomad FIN exome AF: 0.517

Gnomad NFE exome AF: 0.519

Gnomad OTH exome AF: 0.485

GnomAD4 exome AF: 0.496 AC: 714316 AN: 1439874 Hom.: 179990 Cov.: 87 AF XY: 0.494 AC XY: 353224 AN XY: 714592

Gnomad4 AFR exome AF: 0.297

Gnomad4 AMR exome AF: 0.376

Gnomad4 ASJ exome AF: 0.592

Gnomad4 EAS exome AF: 0.386

Gnomad4 SAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.512

Gnomad4 NFE exome AF: 0.515

Gnomad4 OTH exome AF: 0.497

GnomAD4 genome AF: 0.439 AC: 66786 AN: 152052 Hom.: 15453 Cov.: 33 AF XY: 0.438 AC XY: 32592 AN XY: 74336

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.410

Gnomad4 ASJ AF: 0.598

Gnomad4 EAS AF: 0.382

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.520

Gnomad4 OTH AF: 0.447

Alfa AF: 0.504 Hom.: 6230

Bravo AF: 0.425

TwinsUK AF: 0.512 AC: 1898

ALSPAC AF: 0.503 AC: 1940

ESP6500AA AF: 0.284 AC: 1238

ESP6500EA AF: 0.512 AC: 4378

ExAC AF: 0.433 AC: 51499

Asia WGS AF: 0.385 AC: 1341 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary acrodermatitis enteropathica Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

not specified Benign:1

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	8.3
Dann	Benign	0.93
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.000020	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.17	N;N
REVEL	Benign	0.059
Sift	Benign	1.0	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.43	.;B
Vest4		0.047
MPC		0.20
ClinPred		0.0093	T
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17855765; hg19: chr8-145641328; COSMIC: COSV52777498; COSMIC: COSV52777498;