NM_130849.4:c.599C>T

Variant names:

• chr8-144415295-G-A
• rs121434287
• NM_130849.4:c.599C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PP5_Very_Strong

The NM_130849.4(SLC39A4):​c.599C>T​(p.Pro200Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,613,194 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001206138: Experimental studies have shown that this missense change affects SLC39A4 function (PMID:14709598, 31979155).; SCV001824960: Functional studies indicate P200L affects the uptake of zinc and suggests the function of the protein may be impaired, with the availability of the protein at the plasma membrane also affected (Wang et al., 2004; Kambe et al., 2009); SCV004113316: Functional studies in mouse models showed that this variant lead to wild-type levels of protein accumulation, however it was associated with increased accumulation of smaller molecular mass forms of protein (Wang et al. 2004. PubMed ID: 14709598). Additional studies in mouse models also showed that this variant had a modest impact on protein function and was overall similar to that of wild-type function (Wang et al. 2004. PubMed ID: 14709598).". Synonymous variant affecting the same amino acid position (i.e. P200P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SLC39A4 NM_130849.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.72
• Publications: 18 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: Genomics England PanelApp, Ambry Genetics, Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen

LOC124902041 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001206138: Experimental studies have shown that this missense change affects SLC39A4 function (PMID: 14709598, 31979155).; SCV001824960: Functional studies indicate P200L affects the uptake of zinc and suggests the function of the protein may be impaired, with the availability of the protein at the plasma membrane also affected (Wang et al., 2004; Kambe et al., 2009); SCV004113316: Functional studies in mouse models showed that this variant lead to wild-type levels of protein accumulation, however it was associated with increased accumulation of smaller molecular mass forms of protein (Wang et al. 2004. PubMed ID: 14709598). Additional studies in mouse models also showed that this variant had a modest impact on protein function and was overall similar to that of wild-type function (Wang et al. 2004. PubMed ID: 14709598).
• PP5: Variant 8-144415295-G-A is Pathogenic according to our data. Variant chr8-144415295-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A4	NM_130849.4	MANE Select	c.599C>T	p.Pro200Leu	missense	Exon 3 of 12	NP_570901.3	Q6P5W5-1
	SLC39A4	NM_017767.3		c.524C>T	p.Pro175Leu	missense	Exon 2 of 11	NP_060237.3	Q6P5W5-2
	SLC39A4	NM_001374839.1		c.317C>T	p.Pro106Leu	missense	Exon 2 of 11	NP_001361768.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A4	ENST00000301305.8	TSL:1 MANE Select	c.599C>T	p.Pro200Leu	missense	Exon 3 of 12	ENSP00000301305.4	Q6P5W5-1
	SLC39A4	ENST00000276833.9	TSL:2	c.524C>T	p.Pro175Leu	missense	Exon 2 of 11	ENSP00000276833.5	Q6P5W5-2
	SLC39A4	ENST00000526658.1	TSL:3	c.317C>T	p.Pro106Leu	missense	Exon 2 of 4	ENSP00000434512.1	E9PQ16

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000128 AC: 32 AN: 249864 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000181 AC: 264 AN: 1460920 Hom.: 0 Cov.: 34 AF XY: 0.000180 AC XY: 131 AN XY: 726776

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.0000949 AC: 5 AN: 52686

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000220 AC: 245 AN: 1111856

Other (OTH) AF: 0.0000828 AC: 5 AN: 60364

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67986

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000122 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Hereditary acrodermatitis enteropathica (2)
1	-	-	SLC39A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.63
MVP		0.77
MPC		0.60
ClinPred		0.43	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.66
Mutation Taster		=28/72	disease causing (ClinVar)

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: rs121434287; hg19: chr8-145640679;