NM_130849.4:c.1888G>C

Variant names:

• chr8-144412594-C-G
• rs1554871810
• NM_130849.4:c.1888G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_130849.4(SLC39A4):​c.1888G>C​(p.Gly630Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G630S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC39A4 NM_130849.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.28
• Publications: 1 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 8-144412594-C-G is Pathogenic according to our data. Variant chr8-144412594-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2433455.Status of the report is criteria_provided_single_submitter, 1 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.1888G>C	p.Gly630Arg	missense	Exon 12 of 12	NP_570901.3	Q6P5W5-1
	SLC39A4	NM_017767.3		c.1813G>C	p.Gly605Arg	missense	Exon 11 of 11	NP_060237.3	Q6P5W5-2
	SLC39A4	NM_001374839.1		c.1606G>C	p.Gly536Arg	missense	Exon 11 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.1888G>C	p.Gly630Arg	missense	Exon 12 of 12	ENSP00000301305.4	Q6P5W5-1
	SLC39A4	ENST00000532718.5	TSL:1	n.488G>C		non_coding_transcript_exon	Exon 4 of 4
	SLC39A4	ENST00000276833.9	TSL:2	c.1813G>C	p.Gly605Arg	missense	Exon 11 of 11	ENSP00000276833.5	Q6P5W5-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary acrodermatitis enteropathica (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.038
Eigen_PC	Benign	-0.088
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-1.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.29
Sift	Benign	0.050	D
Sift4G	Benign	0.37	T
Polyphen		0.95	P
Vest4		0.53
MutPred		0.96		Gain of methylation at G630 (P = 0.0108)
MVP		0.71
MPC		0.49
ClinPred		0.72	D
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.73
gMVP		0.55
Mutation Taster		=9/91	disease causing

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: rs1554871810; hg19: chr8-145637978;