rs121434291

Variant names:

• chr8-144414422-C-T
• rs121434291
• NM_130849.4:c.989G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-144414422-C-T
• chr8-144414422-C-A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_130849.4(SLC39A4):​c.989G>A​(p.Gly330Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G330S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC39A4 NM_130849.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.07
• Publications: 9 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 8-144414422-C-T is Pathogenic according to our data. Variant chr8-144414422-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3542.Status of the report is no_assertion_criteria_provided, 0 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.989G>A	p.Gly330Asp	missense	Exon 6 of 12	NP_570901.3	Q6P5W5-1
	SLC39A4	NM_017767.3		c.914G>A	p.Gly305Asp	missense	Exon 5 of 11	NP_060237.3	Q6P5W5-2
	SLC39A4	NM_001374839.1		c.707G>A	p.Gly236Asp	missense	Exon 5 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.989G>A	p.Gly330Asp	missense	Exon 6 of 12	ENSP00000301305.4	Q6P5W5-1
	SLC39A4	ENST00000276833.9	TSL:2	c.914G>A	p.Gly305Asp	missense	Exon 5 of 11	ENSP00000276833.5	Q6P5W5-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1406750 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 694456

African (AFR) AF: 0.00 AC: 0 AN: 32198

American (AMR) AF: 0.00 AC: 0 AN: 35906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25228

East Asian (EAS) AF: 0.00 AC: 0 AN: 37096

South Asian (SAS) AF: 0.00 AC: 0 AN: 79862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5450

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083740

Other (OTH) AF: 0.00 AC: 0 AN: 58342

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.93		Loss of catalytic residue at Y329 (P = 0.0954)
MVP		0.72
MPC		0.65
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.75
gMVP		0.80
Mutation Taster		=18/82	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: rs121434291; hg19: chr8-145639806;